Top Leaderboard Ranking = Top Coding Proficiency, Always? EvoEval: Evolving Coding Benchmarks via LLM

Abstract: LLMs have become the go-to choice for code generation tasks, with an exponential increase in the training, development, and usage of LLMs specifically for code generation. To evaluate the ability of LLMs on code, both academic and industry practitioners rely on popular handcrafted benchmarks. However, prior benchmarks contain only a very limited set of problems, both in quantity and variety. Further, due to popularity and age, many benchmarks are prone to data leakage where example solutions can be readily found on the web and thus potentially in training data. Such limitations inevitably lead us to inquire: Is the leaderboard performance on existing benchmarks reliable and comprehensive enough to measure the program synthesis ability of LLMs? To address this, we introduce EvoEval -- a program synthesis benchmark suite created by evolving existing benchmarks into different targeted domains for a comprehensive evaluation of LLM coding abilities. Our study on 51 LLMs shows that compared to the high performance obtained on standard benchmarks like HumanEval, there is a significant drop in performance (on average 39.4%) when using EvoEval. Additionally, the decrease in performance can range from 19.6% to 47.7%, leading to drastic ranking changes amongst LLMs and showing potential overfitting of existing benchmarks. Furthermore, we showcase various insights, including the brittleness of instruction-following models when encountering rewording or subtle changes as well as the importance of learning problem composition and decomposition. EvoEval not only provides comprehensive benchmarks, but can be used to further evolve arbitrary problems to keep up with advances and the ever-changing landscape of LLMs for code. We have open-sourced our benchmarks, tools, and complete LLM generations at https://github.com/evo-eval/evoeval


RLTF: Reinforcement Learning from Unit Test Feedback

Abstract: The goal of program synthesis, or code generation, is to generate executable code based on given descriptions. Recently, there has been an increasing number of studies employing reinforcement learning (RL) to improve the performance of large language models (LLMs) for code. However, current representative works either rely solely on offline frameworks, limiting the exploration of new sample spaces, or fall short in the utilization of unit test signals, not accounting for specific error locations within the code. To address these issues, we propose RLTF, i.e., Reinforcement Learning from Unit Test Feedback, a novel online RL framework with unit test feedback of multi-granularity for refining code LLMs. Our approach generates data in real-time during training and simultaneously utilizes fine-grained feedback signals to guide the model towards producing higher-quality code. Extensive experiments show that RLTF achieves state-of-the-art performance on the APPS and the MBPP benchmarks. Our code is available at: https://github.com/Zyq-scut/RLTF.


Synergizing human expertise and AI efficiency with language model for microscopy operation and automated experiment design

Abstract: With the advent of large language models (LLMs), in both the open source and proprietary domains, attention is turning to how to exploit such artificial intelligence (AI) systems in assisting complex scientific tasks, such as material synthesis, characterization, analysis and discovery. Here, we explore the utility of LLMs, particularly ChatGPT4, in combination with application program interfaces (APIs) in tasks of experimental design, programming workflows, and data analysis in scanning probe microscopy, using both in-house developed APIs and APIs given by a commercial vendor for instrument control. We find that the LLM can be especially useful in converting ideations of experimental workflows to executable code on microscope APIs. Beyond code generation, we find that the GPT4 is capable of analyzing microscopy images in a generic sense. At the same time, we find that GPT4 suffers from an inability to extend beyond basic analyses for more in-depth technical experimental design. We argue that an LLM specifically fine-tuned for individual scientific domains can potentially be a better language interface for converting scientific ideations from human experts to executable workflows. Such a synergy between human expertise and LLM efficiency in experimentation can open new doors for accelerating scientific research, enabling effective experimental protocols sharing in the scientific community.

Machine Learning: Science and Technology


ReGAL: Refactoring Programs to Discover Generalizable Abstractions

Abstract: While large language models (LLMs) are increasingly being used for program synthesis, they lack the global view needed to develop useful abstractions; they generally predict programs one at a time, often repeating the same functionality. Generating redundant code from scratch is both inefficient and error-prone. To address this, we propose Refactoring for Generalizable Abstraction Learning (ReGAL), a gradient-free method for learning a library of reusable functions via code refactorization, i.e., restructuring code without changing its execution output. ReGAL learns from a small set of existing programs, iteratively verifying and refining its abstractions via execution. We find that the shared function libraries discovered by ReGAL make programs easier to predict across diverse domains. On five datasets -- LOGO graphics generation, Date reasoning, TextCraft (a Minecraft-based text-game) MATH, and TabMWP -- both open-source and proprietary LLMs improve in accuracy when predicting programs with ReGAL functions. For CodeLlama-13B, ReGAL results in absolute accuracy increases of 11.5% on LOGO, 26.1% on date understanding, and 8.1% on TextCraft, outperforming GPT-3.5 in two of three domains. Our analysis reveals ReGAL's abstractions encapsulate frequently-used subroutines as well as environment dynamics.

International Conference on Machine Learning


Statically Contextualizing Large Language Models with Typed Holes

Abstract: Large language models (LLMs) have reshaped the landscape of program synthesis. However, contemporary LLM-based code completion systems often hallucinate broken code because they lack appropriate code context, particularly when working with definitions that are neither in the training data nor near the cursor. This paper demonstrates that tighter integration with the type and binding structure of the programming language in use, as exposed by its language server, can help address this contextualization problem in a token-efficient manner. In short, we contend that AIs need IDEs, too! In particular, we integrate LLM code generation into the Hazel live program sketching environment. The Hazel Language Server is able to identify the type and typing context of the hole that the programmer is filling, with Hazel’s total syntax and type error correction ensuring that a meaningful program sketch is available whenever the developer requests a completion. This allows the system to prompt the LLM with codebase-wide contextual information that is not lexically local to the cursor, nor necessarily in the same file, but that is likely to be semantically local to the developer’s goal. Completions synthesized by the LLM are then iteratively refined via further dialog with the language server, which provides error localization and error messages. To evaluate these techniques, we introduce MVUBench, a dataset of model-view-update (MVU) web applications with accompanying unit tests that have been written from scratch to avoid data contamination, and that can easily be ported to new languages because they do not have large external library dependencies. These applications serve as challenge problems due to their extensive reliance on application-specific data structures. Through an ablation study, we examine the impact of contextualization with type definitions, function headers, and errors messages, individually and in combination. We find that contextualization with type definitions is particularly impactful. After introducing our ideas in the context of Hazel, a low-resource language, we duplicate our techniques and port MVUBench to TypeScript in order to validate the applicability of these methods to higher-resource mainstream languages. Finally, we outline ChatLSP, a conservative extension to the Language Server Protocol (LSP) that language servers can implement to expose capabilities that AI code completion systems of various designs can use to incorporate static context when generating prompts for an LLM.

Proceedings of the ACM on Programming Languages


HumanEval on Latest GPT Models - 2024

Abstract: In 2023, we are using the latest models of GPT-4 to advance program synthesis. The large language models have significantly improved the state-of-the-art for this purpose. To make these advancements more accessible, we have created a repository that connects these models to Huamn Eval. This dataset was initally developed to be used with a language model called CODEGEN on natural and programming language data. The utility of these trained models is showcased by demonstrating their competitive performance in zero-shot Python code generation on HumanEval tasks compared to previous state-of-the-art solutions. Additionally, this gives way to developing more multi-step paradigm synthesis. This benchmark features 160 diverse problem sets factorized into multistep prompts that our analysis shows significantly improves program synthesis over single-turn inputs. All code is open source at https://github.com/daniel442li/gpt-human-eval .


Large Language Models Synergize with Automated Machine Learning

Abstract: Recently, program synthesis driven by large language models (LLMs) has become increasingly popular. However, program synthesis for machine learning (ML) tasks still poses significant challenges. This paper explores a novel form of program synthesis, targeting ML programs, by combining LLMs and automated machine learning (autoML). Specifically, our goal is to fully automate the generation and optimization of the code of the entire ML workflow, from data preparation to modeling and post-processing, utilizing only textual descriptions of the ML tasks. To manage the length and diversity of ML programs, we propose to break each ML program into smaller, manageable parts. Each part is generated separately by the LLM, with careful consideration of their compatibilities. To ensure compatibilities, we design a testing technique for ML programs. Unlike traditional program synthesis, which typically relies on binary evaluations (i.e., correct or incorrect), evaluating ML programs necessitates more than just binary judgments. Our approach automates the numerical evaluation and optimization of these programs, selecting the best candidates through autoML techniques. In experiments across various ML tasks, our method outperforms existing methods in 10 out of 12 tasks for generating ML programs. In addition, autoML significantly improves the performance of the generated ML programs. In experiments, given the textual task description, our method, Text-to-ML, generates the complete and optimized ML program in a fully autonomous process. The implementation of our method is available at https://github.com/JLX0/llm-automl.


BatFix: Repairing language model-based transpilation

Abstract: To keep up with changes in requirements, frameworks, and coding practices, software organizations might need to migrate code from one language to another. Source-to-source migration, or transpilation, is often a complex, manual process. Transpilation requires expertise both in the source and target language, making it highly laborious and costly. Languages models for code generation and transpilation are becoming increasingly popular. However, despite capturing code-structure well, code generated by language models is often spurious and contains subtle problems. We propose BatFix, a novel approach that augments language models for transpilation by leveraging program repair and synthesis to fix the code generated by these models. BatFix takes as input both the original program, the target program generated by the machine translation model, and a set of test cases and outputs a repaired program that passes all test cases. Experimental results show that our approach is agnostic to language models and programming languages. BatFix can locate bugs spawning multiple lines and synthesize patches for syntax and semantic bugs for programs migrated from Java to C++ and Python to C++ from multiple language models, including, OpenAI’s Codex.

ACM Transactions on Software Engineering and Methodology


Biomarker Testing, Targeted Therapy and Clinical Trial Participation by Race Among Patients With Lung Cancer: A Real-World Medicaid Database Study

Abstract: Introduction Biomarker testing in oncology is fundamental for targeted therapy use and clinical trial participation. Factors contributing to previously identified racial disparities in biomarker testing remain unclear. This study investigated biomarker testing, clinical trial participation, and targeted therapy by race among patients with metastatic lung cancer with Medicaid coverage in the United States. Methods The Merative MarketScan Medicaid claims database was used for this study to identify patients diagnosed with having metastatic lung cancer between 2017 and 2019 with at least 121 days of follow-up. Racial differences in biomarker testing, clinical trial enrollment, and targeted therapy use were analyzed using chi-square/t tests followed by logistic regression for confounding covariates. Results A total of 3845 patients were eligible. A total of 970 (25.2%) patients included in this study were Black. Biomarker testing was observed among 57.0%, targeted therapy among 4.6%, and 2.6% of the study cohort had evidence of clinical trial participation. No significant disparities between Black and White races were identified. Younger age and metastatic disease at initial diagnosis were the strongest independent factors associated with increased biomarker testing. Biomarker testing was positively associated with targeted therapy use (OR = 1.69, p = 0.005). Conclusions Patients with metastatic lung cancer with Medicaid coverage were found to have exceedingly low biomarker testing rates; only 57% had evidence of any biomarker testing. Although no consistent differences between Black and White races were identified, this study calls attention to care experienced by socioeconomically disadvantaged patients with metastatic lung cancer in the United States.


Liquid biopsy, big data and artificial intelligence as a new global clinical trial model in targeted therapy

Abstract: To this day, the phase III trial continues to be, as it was more than 60 years ago, the standard for the incorporation of new treatments in oncology. We currently have new tools such as NGS, Liquid Biopsy (LB), Big Data (BD) and Artificial Intelligence (AI) that will allow us to move towards faster and more universal research. This article analyzes the important weaknesses of phase III trials, the importance and current status of targeted therapy, and the contributions to LB decision-making and the knowledge of what happens in real life (RWD) that we facilitates BD and AI. Finally, what could be a clinical trial model that would take advantage of all these tools is proposed.


Impact of pharmacist consultation at clinical trial inclusion: an effective way to reduce drug–drug interactions with oral targeted therapy


A randomized trial of consolidation-targeted adjuvant therapy with encorafenib and cetuximab versus usual care for patients with stage II/III BRAF V600E colon cancer: Alliance for Clinical Trials in Oncology A022004.

Abstract: TPS3641 Background: Patients with mismatch repair proficient (pMMR) BRAF V600E mutant high-risk stage II (T4) or stage III colon cancer have a substantial risk of recurrence despite standard adjuvant therapy. In patients with metastatic BRAF V600E mutant colorectal cancer, the combination of the RAF inhibitor encorafenib and the EGFR inhibitor cetuximab has been shown to improve overall and progression-free survival compared to standard therapy after at least one prior line of therapy. This study will evaluate if this combination improves disease-free survival (DFS) in patients with resected BRAF V600E mutant pMMR/microsatellite stable (MSS) high-risk stage II (T4) or stage III colon cancer after standard adjuvant therapy. Methods: The study has a seamless phase II/III design, enrolling a maximum of 394 patients. BRAF mutation status can be determined locally or submitted for central testing in trial pre-screening. Eligible patients will be randomized 1:1 to usual surveillance versus 6 months of treatment with encorafenib (300mg oral daily) plus cetuximab (500mg/m2 intravenous every 14 days). Stratification factors are adjuvant chemotherapy regimen (FOLFOX versus CAPOX), duration of adjuvant therapy (3 months versus > 3 months), tumor stage (T4N0 versus T1-3N1 versus T4N1/TanyN2), and ctDNA marker status (detectable versus undetectable) at randomization. Adjuvant therapy must be completed at most 8 weeks prior to registration. For the phase II component, in the ctDNA detectable cohort, the primary endpoint will be ctDNA clearance rate at 6 months, and, in the ctDNA undetectable cohort, the primary endpoint will be 6-month ctDNA recurrence-free survival, where events consist of death, recurrence, or ctDNA positivity. The primary endpoint of the phase III component is DFS, and secondary endpoints are overall survival, adverse events, and alternative DFS calculated from the date of primary resection, rather than date of study randomization. Patient reported symptoms (PRO-CTCAE) will be collected and analyzed as an exploratory endpoint, and serial blood banking will support future correlative studies. The trial will proceed to the phase III portion if either of the two endpoints in the phase II cohorts is statistically superior in patients receiving encorafenib plus cetuximab. The phase III study sample size will provide 80% power at a one-sided α of 0.05 to detect an approximately 10% improvement in the three-year DFS rate, assuming 68% in the control arm. Two interim analyses will be performed for DFS endpoint. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Pfizer, Eli Lilly; Clinicaltrials.gov ID: NCT05710406. Clinical trial information: NCT05710406 .


A phase I clinical trial of sonodynamic therapy combined with temozolomide in the treatment of recurrent glioblastoma


Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors

Abstract: Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors. In the observational SCRUM-Japan GOZILA study, after a median follow-up of 11 months, patients with metastatic gastrointestinal tumors who received biomarker-matched therapies based on circulating tumor DNA profiling showed a greater clinical benefit than those receiving unmatched therapy.


Toxicity and Efficacy of Local Ablative, Image-guided Radiotherapy in Gallium-68 Prostate-specific Membrane Antigen Targeted Positron Emission Tomography-staged, Castration-sensitive Oligometastatic Prostate Cancer: The OLI-P Phase 2 Clinical Trial.

Abstract:
BACKGROUND
Local ablative radiotherapy (aRT) of oligometastatic prostate cancer (PCa) is very promising and has become a focus of current clinical research.

OBJECTIVE
We hypothesize that aRT is safe and effective in gallium-68 prostate-specific membrane antigen targeted positron emission tomography (PSMA-PET)-staged oligometastatic PCa patients.

DESIGN, SETTING, AND PARTICIPANTS
A nonrandomized, prospective, investigator-initiated phase 2 trial recruited patients with oligometastatic PCa (five or fewer lymph node or osseous metastases) after local curative therapy, without significant comorbidity and androgen deprivation therapy (ADT), at two German centers from 2014 to 2018.

INTERVENTION
All PSMA-PET-positive metastases were treated with aRT. No systemic therapy was initiated.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary endpoint was treatment-related toxicity (grade ≥2) 24 mo after aRT. A one-sided single-sample test of proportions was planned to test whether the endpoint occurs in <15% of the patients. Key secondary endpoints were time to progression of prostate-specific antigen (PSA) and time to ADT, which were associated with potential prognostic factors by Cox regression.

RESULTS AND LIMITATIONS
Of 72 patients, 63 received aRT (13% dropout rate). The median follow-up was 37.2 mo. No treatment-related grade ≥2 toxicity was observed 2 yr after treatment. The median time to PSA progression and time to ADT were 13.2 and 20.6 mo, respectively. Of the patients, 21.4% were free of PSA progression after 3 yr.

CONCLUSIONS
It was observed that aRT is safe, and midterm PSA progression and ADT-free time were achieved in one of five patients. Randomized clinical trials are indicated to further evaluate the option of delaying ADT in selected patients.

PATIENT SUMMARY
In this clinical trial, 63 patients with up to five metastases of prostate cancer without androgen deprivation therapy were included. We showed that local ablative radiotherapy is safe and that one in five patients had no recurrent prostate-specific antigen value after 3 yr. Local ablative radiotherapy might be an option to avoid systemic therapy in selected patients.


Systematic Next Generation Sequencing is feasible in clinical practice and identifies opportunities for targeted therapy in women with uterine cancer: Results from a prospective cohort study.

Abstract:
BACKGROUND
Both incidence and mortality of uterine cancer are on the rise and mortality is higher for African American women. The aim of our study was to evaluate how Next Generation Sequencing (NGS) may facilitate identification of and intervention for treatment disparities when integrated into clinical workflows.

RESULTS
Our cohort included 159 uterine cancer patients with recurrent/progressive and newly diagnosed advanced stage and/or high-risk histology. The most common tumor histological subtypes included EEC (n = 67), SEC (n = 34), UCS (n = 20), and mixed (n = 14). Black patients were most likely to present with aggressive histology: (SEC, 34.0%) and carcinosarcoma (UCS, 14.0%). The four most common mutations across all subtypes were TP53, PIK3CA, PTEN, and ARID1A. There was racial disparity between Black versus non-Black patients who were initiated on targeted therapy (28.2% vs. 38.2%, respectively) and clinical trial (15% vs. 22.6%, respectively). Compared to non-Black patients, Black patients had a significantly higher percentage TP53 mutations (p < 0.05) and a significantly lower percentage ARID1A mutations (p < 0.05).

CONCLUSIONS
NGS for uterine malignancies provides actionable information for targetable mutations and/or clinical trial enrollment in most patients; further investigation is necessary to identify potentially modifiable factors contributing to current disparities that may improve targeted therapy uptake and clinical trial participation.


Durvalumab, tremelimumab alone or in combination with low-dose or hypofractionated targeted radiotherapy in metastatic non-small cell lung cancer refractory to prior PD(L)-1 therapy: a multicentre, open-label, randomised, phase 2 trial

Abstract: Summary Background Patients with PD(L)-1 therapy resistant non-small cell lung cancer (NSCLC) have poor outcomes. Studies suggest radiotherapy may enhance anti-tumor immunity. Therefore, we investigated combined PD-L1 (durvalumab) and CTLA-4 inhibition (tremelimumab) alone or combined with radiation. Methods This multicentre, randomised, open-label phase 2 NCI Experimental Therapeutics Clinical Trials Network trial was conducted at 18 U.S. sites. Patients aged >=18 years with metastatic NSCLC, Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were randomised (1:1:1) using a permuted block scheme, without stratification to durvalumab/tremelimumab (1500mg/75mg every 4 weeks, 4 cycles, intravenous) alone (noRT) or with low-dose (LDFRT) or hypofractionated (HFRT) radiotherapy followed by durvalumab until 52 weeks or progression. The primary endpoint was the rate of complete/partial response in patients who initiated study treatment. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete. Findings 90 patients were randomised and 78 patients treated between 24 August 2017 and 29 March 2019. Median follow up was 12.4 months (IQR 7.8-15.1). There were no differences in response rates between the noRT arm (3 [11.5%] of 26, 90% CI 1.2-21.8) and the LDFRT (2 [7.7%] of 26, 0-16.3, p=0.64) or HFRT (3 [11.5%] of 26, 90% CI 1.2-21.8, p=0.99) arms. The most common grade 3-4 adverse event was dyspnea (2 [8%] of 26 NoRT, 3 [11%] LDFRT, and 3 [11%] HFRT). Serious adverse events occurred in 4 (15%, NoRT), 8 (31%, LDFRT) and 3 (12%, HFRT) patients. There was 1 grade-5 respiratory failure potentially related to therapy (LDFRT arm). Interpretation Radiation should not be used to increase response to PD-L1/CTLA-4 inhibition in PD(L)-1-resistant NSCLC patients. However, PD-L1/CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting. Funding: US National Institutes of Health, Dana-Farber Cancer Institute


The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in immune-oncology era (SEVURO-CN): study protocol for a multi-center, prospective, randomized trial

Abstract: Background The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear in the immuno-oncology (IO) era. The results of two randomized trials, CARMENA and SURTIME, questioned the role and timing of CN. However, despite the latest advances in the systemic treatment of mRCC, previous trials have only used targeted therapy, and no studies have fully investigated the role of CN in immune checkpoint inhibitor (CPI) settings, and there is an urgent need for future studies to better define the role and timing of CN. Methods This study is an open-label, multi-center, parallel, prospective, randomized, interventional clinical study to evaluate the efficacy of CN in combination with CPIs in mRCC patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk. Synchronous mRCC patients with ≤ 3 IMDC risk features will be randomly allocated to three groups (1, upfront CN; 2, deferred CN; and 3, systemic therapy [ST] only). For ST, the nivolumab plus ipilimumab combination regimen, one of the standard regimens for intermediate- and poor-risk mRCC, is chosen. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, objective response rate, number of participants with treatment-related adverse events, and number of participants with surgical morbidity. We will analyze the genetic mutation profiles of the tumor tissue, circulating tumor DNA, urine tumor DNA, and tumor-infiltrating lymphocytes. The gut and urine microbial communities will be analyzed. The study will begin in 2022 and will enroll 55 patients. Discussion This study is one of the few prospective randomized trials to evaluate the benefit of CN in the treatment of synchronous mRCC in the IO era. The SEVURO-CN trial will help identify the role and timing of CN, thereby rediscovering the value of CN. Trial registration ClinicalTrials.gov, NCT05753839. Registered on 3 March 2023.


Targeting Inhibitor of Apoptosis Proteins to Overcome Chemotherapy Resistance—A Marriage between Targeted Therapy and Cytotoxic Chemotherapy

Abstract: Precision oncology is the ultimate goal of cancer treatment, i.e., to treat cancer and only cancer, leaving all the remaining cells and tissues as intact as possible. Classical chemotherapy and radiotherapy, however, are still effective in many patients with cancer by effectively inducing apoptosis of cancer cells. Cancer cells might resist apoptosis via the anti-apoptotic effects of the inhibitor of apoptosis proteins. Recently, the inhibitors of those proteins have been developed with the goal of enhancing the cytotoxic effects of chemotherapy and radiotherapy, and one of them, xevinapant, has already demonstrated effectiveness in a phase II clinical trial. This class of drugs represents an example of synergism between classical cytotoxic chemo- and radiotherapy and new targeted therapy.

International Journal of Molecular Sciences


The role of molecular biomarkers in recurrent glioblastoma trials: an assessment of the current trial landscape of genome-driven oncology

Abstract: For glioblastoma patients, the efficacy-targeted therapy is limited to date. Most of the molecular therapies previously studied are lacking efficacy in this population. More trials are needed to study the actual actionability of biomarkers in (recurrent) glioblastoma. This study aimed to assess the current clinical trial landscape to assess the role of molecular biomarkers in trials on recurrent glioblastoma treatment. The database ClinicalTrials.gov was used to identify not yet completed clinical trials on recurrent glioblastoma in adults. Recruiting studies were assessed to investigate the role of molecular criteria, which were retrieved as detailed as possible. Primary outcome was molecular criteria used as selection criteria for study participation. Next to this, details on moment and method of testing, and targets and drugs studied, were collected. In 76% (181/237) of the included studies, molecular criteria were not included in the study design. Of the remaining 56 studies, at least one specific genomic alteration as selection criterium for study participation was required in 33 (59%) studies. Alterations in EGFR, CDKN2A/B or C, CDK4/6, and RB were most frequently investigated, as were the corresponding drugs abemaciclib and ribociclib. Of the immunotherapies, CAR-T therapies were the most frequently studied therapies. Previously, genomics studies have revealed the presence of potentially actionable alterations in glioblastoma. Our study shows that the potential efficacy of targeted treatment is currently not translated into genome-driven trials in patients with recurrent glioblastoma. An intensification of genome-driven trials might help in providing evidence for (in)efficacy of targeted treatments.

Medical Oncology (Northwood, London, England)


Targeted therapy in advanced non-small cell lung cancer: current advances and future trends

Abstract: Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patients at the end of each section.


The role of immunotherapy and targeted therapy in the multimodal therapy for resectable lung cancer

Abstract: As the immunotherapeutic milieu in resectable nonsmall cell lung cancer continues to evolve, the field of thoracic oncology actively moves towards better patient selection based on biomarkers and oncogenic drivers. In this article, we review the current standard of oncologic care in this population and discuss the ongoing phase III clinical trials investigating the use of immunotherapy or targeted therapy in the perioperative period. We also discuss genotyping initiatives, biomarkers, and trial endpoints.


Impact of a Clinical Genomics Program on Trial Accrual for Targeted Treatments: Practical Approach Overcoming Barriers to Accrual for Underserved Patients.

Abstract:
PURPOSE
Clinical trials of novel and targeted agents increasingly require biomarkers for eligibility. Precision oncology continues to evolve, but challenges hamper broad use of molecular profiling (MP) that could increase the number of patients benefiting from targeted therapy. We implemented an integrated clinical genomics program (CGP), including a virtual Molecular Tumor Board (MTB), and examined its impact on MP use and impact on clinical trial accrual in a multisite regional-based cancer system with an emphasis on effects for isolated clinicians.

METHODS
We assessed MP and MTB use from 2010 to 2020 by practice location, physician experience, and patient characteristics. Use of MTB-recommended treatments was assessed. Clinical trial enrollment was evaluated for patients with MP versus MP and MTB review.

RESULTS
After CGP implementation, the number of physicians using MP and the number of MP tests increased ≥ 10-fold. The proportion of Hispanic patients with MP was the same as that in the system (both 2%) with marginal differences observed in the proportion of African Americans tested compared with the system population (16% v 19%). Physicians followed MTB treatment recommendations in 74% of cases. Rapid clinical decline was the most common reason why physicians did not follow MTB recommendations. Clinical trial accrual was 15% (669 of 4,459) for patients with MP alone and 28% (94 of 334) with both MP and MTB review. Clinical trial availability and patient out-of-pocket costs affected MP use.

CONCLUSION
Integrating CGP into clinical workflow with decision support tools, trial matching, and management of patient costs led to increased use of MP by physicians with all levels of experience, enhanced clinical trial accrual, and has the potential to reduce disparities in MP.


Clinical utility of targeted next generation sequencing assay in IDH-wildtype glioblastoma for therapy decision-making.

Abstract:
BACKGROUND
Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center.

METHODS
We identified 1,011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013-2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results.

RESULTS
Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a post hoc analysis.

CONCLUSIONS
While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.


Molecular Tumor Board–Assisted Care in an Advanced Cancer Population: Results of a Phase II Clinical Trial

Abstract: PURPOSE Multidisciplinary molecular tumor boards (MTBs) interpret next-generation sequencing reports and help oncologists determine best therapeutic options; however, there is a paucity of data regarding their clinical utility. The purpose of this study was to determine if MTB-directed therapy improves progression-free survival (PFS) over immediately prior therapy in patients with advanced cancer. METHODS This single-arm, prospective phase II clinical trial enrolled patients with advanced cancer with an actionable mutation who received MTB-recommended targeted therapy between January 1, 2017, and October 31, 2020. MTB-recommended both on-label (level 1 evidence) and off-label (evidence levels 2 and 3) therapies. Of the 93 enrolled patients, 43 were treated frontline and 50 received second-line or greater-line therapy. The primary outcome was the probability of patients treated with second-line or greater-line MTB-directed therapy who achieved a PFS ratio ≥ 1.3 (PFS on MTB-directed therapy divided by PFS on the patient's immediately prior therapy). Secondary outcomes included PFS for patients treated frontline and overall survival and adverse effects for the entire study population. RESULTS The most common disease sites were lung (35 of 93, 38%), gynecologic (17 of 93, 18%), GI (16 of 93, 17%), and head and neck (7 of 93, 8%). The Kaplan-Meier estimate of the probability of PFS ratio ≥ 1.3 was 0.59 (95% CI, 0.47 to 0.75) for patients treated with second-line or greater-line MTB-directed therapy. The median PFS was 449 (range 42-1,125) days for patients treated frontline. The median overall survival was 768 (range 22-1,240) days. There were four nontreatment-related deaths. CONCLUSION When treated with MTB-directed therapy, most patients experienced improved PFS compared with immediately prior treatment. MTB-directed targeted therapy may be a strategy to improve outcomes for patients with advanced cancer.


Pemigatinib: Hot topics behind the first approval of a targeted therapy in cholangiocarcinoma.

Abstract: Cholangiocarcinoma (CCA) includes a heterogeneous group of malignancies with limited treatment options. Despite recent advances in medical oncology, the prognosis of CCA patients with metastatic disease remains poor, with a median overall survival of less than a year. In the last decade, notable efforts have been made by the CCA medical community in an attempt to improve clinical outcomes of patients, with the development of molecularly targeted therapies in this setting. Among these treatments, the fibroblast growth factor receptor (FGFR) 2 inhibitor pemigatinib has received accelerated approval in April 2020 by the US Food and Drug Administration (FDA) in CCA patients harboring FGFR2 gene fusions or other rearrangements, on the basis of the results of the FIGHT-202 trial, and thus, representing the first molecularly targeted therapy to be approved for the treatment of CCA. However, several issues remain, including the emergence of polyclonal mutations determining resistance to pemigatinib, the identification of biomarkers predictive of response, and the knowledge gaps regarding the role of other FGFR gene aberrations. This review aims to provide an overview of recent development of pemigatinib, especially focusing on the results of the pivotal FIGHT-202 trial, the approval of this FGFR inhibitor, and the future challenges concerning the use of FGFR-directed treatments in CCA patients.

Cancer Treatment and Research Communications

Cancer treatment and research communications


Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies.

Abstract:
Importance
The number of new genome-targeted cancer drugs has increased, offering the possibility of personalized therapy, often at a very high cost.

Objective
To assess the validity of molecular targets and therapeutic benefits of US Food and Drug Administration-approved genome-targeted cancer drugs based on the outcomes of their corresponding pivotal clinical trials.

Design and Settings
In this cohort study, all genome-targeted cancer drugs that were FDA-approved between January 1, 2015, and December 31, 2022, were analyzed. From FDA drug labels and trial reports, key characteristics of pivotal trials were extracted, including the outcomes assessed.

Main Outcomes and Measures
The strength of evidence supporting molecular targetability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit for their approved indications was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Substantial clinical benefit was defined as a grade of A or B for curative intent and 4 or 5 for noncurative intent. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-based cancer treatments.

Results
A total of 50 molecular-targeted drugs covering 84 indications were analyzed. Forty-five indications (54%) were approved based on phase 1 or phase 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials, and 48 (57%) were approved on the basis of subgroup analyses. By each indication, 46 of 84 primary end points (55%) were overall response rate (median [IQR] overall response rate, 57% [40%-69%]; median [IQR] duration of response, 11.1 [9.2-19.8] months). Among the 84 pivotal trials supporting these 84 indications, 38 trials (45%) had I-A ESCAT targetability, and 32 (38%) had I-B targetability. Overall, 24 of 84 trials (29%) demonstrated substantial clinical benefit via ESMO-MCBS. Combining these ratings, 24 of 84 indications (29%) were associated with high-benefit genomic-based cancer treatments.

Conclusions and Relevance
The results of this cohort study demonstrate that among recently approved molecular-targeted cancer therapies, fewer than one-third demonstrated substantial patient benefits at approval. Benefit frameworks such as ESMO-MCBS and ESCAT can help physicians, patients, and payers identify therapies with the greatest clinical potential.


Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials

Abstract: Metastatic prostate cancer continues to be an incurable disease. Despite all the novel therapies approved in the past two decades, overall patient outcomes remain relatively poor, and these patients die on a regular basis. Clearly, improvements in current therapies are needed. Prostate-specific membrane antigen (PSMA) is a target for prostate cancer given its increased expression on the surface of the prostate cancer cells. PSMA small molecule binders include PSMA-617 and PSMA-I&T and monoclonal antibodies such as J591. These agents have been linked to different radionuclides including beta-emitters such as lutetium-177 and alpha-emitters such as actinium-225. The only regulatory-approved PSMA-targeted radioligand therapy (PSMA-RLT) to date is lutetium-177–PSMA-617 in the setting of PSMA-positive metastatic castration-resistant prostate cancer that has failed androgen receptor pathway inhibitors and taxane chemotherapy. This approval was based on the phase III VISION trial. Many other clinical trials are evaluating PSMA-RLT in various settings. Both monotherapy and combination studies are underway. This article summarizes pertinent data from recent studies and provides an overview of human clinical trials in progress. The field of PSMA-RLT is rapidly evolving, and this therapeutic approach will likely play an increasingly important role in the years to come.

Therapeutic Advances in Medical Oncology


Targeted therapy moves to earlier stages of non-small-cell lung cancer: emerging evidence, controversies and future challenges.

Abstract: Lung cancer continues to be the leading cause of cancer mortality and a serious health problem despite the numerous advances made in the last decade and the rapid advance of research in this field. In recent years, there has been a decrease in mortality from lung cancer coinciding with the approval times of targeted therapy. To date, targeted therapy has been used in the context of advanced disease in clinical practice, with great benefits in survival and quality of life. The next step will be to incorporate targeted therapy into the treatment of earlier stages of non-small-cell lung cancer, and there is already a randomized trial showing a disease-free survival benefit. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of targeted therapies in nonmetastatic disease.


Preliminary efficacy and safety of Relmacabtagene autoleucel (Carteyva) in adults with relapsed/refractory follicular lymphoma in China: A phase I/II clinical trial

Abstract: To the Editor: Follicular lymphoma (FL) is an indolent B cell lymphoproliferative disorder and the second most common type of non-Hodgkin lymphoma. The recent development of chimeric antigen receptor (CAR)-T cell therapy has provided a novel and effective treatment strategy for patients with relapsed/refractory (r/r) FL. Relmacabtagene autoleucel (relma-cel, also known as Carteyva and JWCAR029) is a secondgeneration CD19-targeted CAR-T cell with a 4-1BB co-stimulatory domain that was developed in China. A single-arm, multicenter study in China reported that relma-cel achieved a 3-month ORR of 60.3% in patients with r/r diffuse large B-cell lymphoma (LBCL), and relma-cel is approved by the National Medical Products Administration (NMPA) for the treatment of r/r LBCL. However, the efficacy, safety and optimal dose of relma-cel in patients with r/r FL has yet to be determined. This study analyzed the r/r FL cohort in dose expansion and subjects in dose escalation administrated with either 100 10 or 150 10 CAR-T cells of the RELIANCE trial (NCT04089215), which enrolled patients with LBCL or FL at 6 tertiary hospitals in China. The inclusion criteria of r/r FL cohort were as follows: (1) age ≥ 18 yearsold; (2) grade 1, 2 or 3a FL confirmed histologically within 6 months; (3) treated with anthracyclines and rituximab (or other CD20-targeted therapies); (4) primary r/r disease within 24 months after at least two lines of therapy or autologous hematopoietic stem cell transplantation; and (5) Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–1. Full details of the inclusion and exclusion criteria are provided in Supplementary Methods. All subjects underwent leukapheresis for relma-cel preparation (Figure S1A). Bridging therapy including low-dose chemotherapy or targeted therapy was allowed after leukapheresis, and should be completed 7 days before lymphodepletion chemotherapy. The 3-day lymphodepletion chemotherapy regimen (fludarabine 25 mg/m/day plus cyclophosphamide 250 mg/m/day) was completed 2–7 days before relma-cel infusion. Patients received relma-cel at a fixed dose of either 100 10 CAR-T cells or 150 10 CAR-T cells. Dose adjustments were not generally permitted, and any investigator-agreed adjustment was documented. The primary endpoint of the study was complete response rate (CRR) at 3 months assessed by investigator. Other endpoints are presented in the Supplementary Methods. Based on the primary endpoint and under the null hypothesis assumption of 3-month CRR ≤35% for standard therapy in this setting and an alternative hypothesis assumption of 70% 3-month CRR, with the sample size of 26 patients, this study has 94% power and one-sided α of 0.025. Statistical methods are provided in the Supplementary Methods. Among 30 patients with r/r FL screened for enrollment, 24 patients were treated with relma-cel and included in this study. An additional 4 patients were included from the phase I study. Thus, the final analysis included a total of 28 patients with r/r FL (Figure S1B), among which 9 (32.1%) received bridging therapies. No patient had complete response (CR) following bridging therapy before lymphodepleting chemotherapy. Sixteen patients received 100 10 CAR-T cells, and 12 patients received 150 10 CAR-T cells. The median time from leukapheresis to relma-cel infusion was 34 (range: 24–79) days. One patient treated with relma-cel was diagnosed as a second malignancy (gastric adenocarcinoma). The patient was excluded from the efficacy analysis (n = 27), but included in the safety analysis (n = 28). The median age of the 28 patients was 54 (range: 36–71) years. The baseline characteristics were presented in Table S1. The data cutoff date was December 17, 2021. Among 27 patients in the efficacy analysis, the investigatorassessed 3-month CRR was 85.2% (95% confidence interval [CI]: 66.3%–95.8%) (Figure 1A). The independent review committee (IRC)-assessed 3-month CRR was 81.5% (95% CI: 61.9%–93.7%) and the investigator-assessed 3-month overall response rate (ORR) was 100.0% (95% CI: 87.2%–100.0%) in the entire cohort (Table S2). The investigator-assessed 1-, 6-month and best CRR was 66.7% (95% CI: 46.0%–83.5%), 77.8% (95% CI: 57.7%–91.4%) and 92.9% (95% CI: 76.5%–99.1%), respectively for all patients in the efficacy analysis (Table S2). The time to response was 0.89 (range: 0.76–0.95) month. Among 25 patients with complete response as best response, the time to CR was 0.95 (range: 0.76–12.02) month. The 3-month ORR was 100% in all subgroups and the 3-month CRR was above 60.0% in all subgroups (Figure 1B). With a median follow-up time of 11.7 (range: 5.4–24.7) months, the median duration of response and median progression-free survival were not reached in the overall population or in either of the two dose groups (Figure 1C). No patients died during follow-up. The incidence of treatment-emergent adverse events (TEAEs) was 96.4% in all 28 patients, 93.8% in the 100 10 dose group and 100.0% in the 150 10 dose group (Table S3). The most common TEAEs were leukopenia (78.6%). The incidence of grade ≥3 TEAEs was 64.3% in the entire cohort. The most common grade ≥3 TEAEs were neutropenia (39.3%). The incidence of relma-cel-related Received: 17 June 2022 Revised: 24 August 2022 Accepted: 26 August 2022


NRG-BR002: A phase IIR/III trial of standard of care systemic therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) for newly oligometastatic breast cancer (NCT02364557).

Abstract: 1007 Background: Prospective and retrospective studies of patients (pts) with oligometastatic (OM) disease have supported that metastases (mets) directed treatment (MDT) with SBRT or SR in addition to standard of care systemic therapy (SOC ST) can improve progression-free (PFS) and overall survival (OS) compared with SOC ST alone. However, randomized evidence in oligometastatic breast cancer (OMBC) are lacking. NRG-BR002, a randomized Phase IIR/III trial, sought to determine the efficacy of SOC ST + MDT (SBRT or SR) as first line treatment of OMBC. Methods: OMBC pts with ≤ 4 extracranial mets on standard imaging with controlled primary disease were eligible if on first line SOC ST for ≤ 12 months without progression. Pts were randomized (1:1) to ARM 1 – SOC ST (mainly chemotherapy, endocrine therapy, anti-HER2) or ARM 2 – SOC ST with MDT of all mets. Stratification included mets number (1 vs > 1), ER/PR and Her2 status, and chemotherapy use. Phase IIR targeted sample size was 128 total/116 eligible pts, for 92% power and 1-sided significance level = 0.15 to determine if adding MDT shows a signal for improved PFS (hazard ratio [HR] = 0.55, corresponding to median PFS (mPFS) from 10.5 to 19 months), in order to continue to the full phase III trial for OS. PFS and OS were estimated by Kaplan-Meier and arms compared with log-rank. Results: 125 of the 129 pts randomized were eligible (ARM 1 = 65, ARM 2 = 60). Key characteristics included median age 54, 79% ER+ or PR+/HER2-, 13% HER2+, 8% triple negative. 60% had 1 metastasis and 20% presented synchronously with primary disease. Following randomization, systemic therapy was delivered to 95% in ARM 1 and 93% in ARM 2; ablation: SBRT 93%, SR 2%, and 5% none. The median follow-up was 30 mo. The mPFS (70% CI) in ARM 1 was 23 mo (18, 29) and 19.5 mo (17, 36) in ARM 2; 24 and 36-mo PFS (70% CI) for ARM 1 were 45.7% (38.9, 52.5) and 32.8% (26.0, 39.5) compared with 46.8 (39.2, 54.3) and 38.1 (29.7, 46.6) in ARM 2; HR (70% CI): 0.92 (0.71, 1.17); and 1-sided log-rank p = 0.36. As PFS did not show signal, OS reporting is included: median OS was not reached in either arm; 36-mo OS (95% CI) in ARM 1 71.8% (58.9, 84.7) and ARM 2 68.9% (55.1, 82.6; 2-sided log-rank p = 0.54). Analysis of first failure showed new mets outside index area (Arm 1) /RT field (Arm 2) developed similarly in both arms at 40%. There were fewer new mets inside treated/index area for Arm 2 6.7% vs ARM 1 29.2%, respectively. There were no grade 5 treatment-related adverse events (AEs), 1 grade 4 AE in ARM 1, and 9.7% and 5.3% grade 3 AEs in ARMS 1 and 2, respectively. Circulating tumor cell counts (0 vs ≥1) at baseline were similar in both arms and were not prognostic HR (95% CI): 1.04 (0.54, 2.02). Conclusions: The addition of MDT to SOC ST did not show signal for improved PFS, nor OS difference in patients with OMBC. The trial will not proceed to the Phase III component. Clinical trial information: NCT02364557.


ClinicalOmicsDB: exploring molecular associations of oncology drug responses in clinical trials

Abstract: Abstract Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established ontology for easier navigation. The web application provides users with three options to explore molecular associations of oncology drug responses, focusing on studies, treatments or genes, respectively. Gene set analysis further connects treatment response to pathway activity and tumor microenvironment attributes. The user-friendly web interface of ClinicalOmicsDB streamlines interactive analysis. A Rust-based backend speeds up response time, and application programming interfaces and an R package enable programmatic access. We use three case studies to demonstrate the utility of this resource in human cancer studies. ClinicalOmicsDB is freely available at http://trials.linkedomics.org/.


Efficacy of Neoadjuvant Targeted Therapy in Treatment of Patients with Localised Clear-Cell Renal Cell Carcinoma

Abstract: Aim This study aimed to evaluate the efficacy of neoadjuvant targeted therapy (TT) in patients with localised clear-cell renal cell carcinoma (RCC). Materials and Methods A special randomised trial was planned and conducted by the Research Department of Plastic and Reconstructive Oncology in the National Cancer Institute of Ukraine for testing the clinical efficacy of neoadjuvant TT in the treatment of clear-cell localised RCC, and the primary endpoint was tumour response evaluation after TT. The secondary endpoints included evaluation of dependence between the use of neoadjuvant TT and the probability of partial nephrectomy and the correlation between tumour size, stage, remaining functioning parenchyma volume, and response to systemic therapy. Results Overall, 118 patients met the inclusion criteria and were randomly assigned to receive combined treatment or surgery alone. The percentage of tumour regression ranged from 0% to 60%, and the median was (95% confidence interval) 20.5 ± 14.3 (16.8–24.3%). Most of the patients had a slightly positive response to TT (3%–29% decrease in tumour size); n = 44 (76.9%) cases. Partial response by the Response Evaluation Criteria in Solid Tumours, version 1.1, was observed in 14 (24.1%) patients and reached a maximum of 60% regression. Tumour reduction in the neoadjuvant TT group allowed kidney preservation in 53 (91.4%) patients. In the control group, the number of organ-sparing procedures was significantly lower (n = 20, 33.3%). The statistical difference was relevant (x2 = 42.1; p < 0.001). Conclusion The positive results of neoadjuvant TT obtained in our study indicate the clinical validity of combined treatment in patients with localised RCC.


Larotrectinib: A Targeted Therapy for Solid Tumors.

Abstract:
BACKGROUND
Although neurotrophic tyrosine receptor kinase (NTRK) gene fusions are not common in most cancers, they are present in more than 90% of some rare tumors. The U.S. Food and Drug Administration has approved larotrectinib for patients with NTRK gene fusion-positive cancers that meet certain criteria. With ongoing advancements in tumor sequencing, it is anticipated that cancer treatment will be determined by genetic variants rather than by cancer type in the future.

OBJECTIVES
This article provides an overview of larotrectinib, a targeted therapy.

METHODS
This article reviews clinical trial results and highlights implications for oncology nurses caring for patients taking larotrectinib.

FINDINGS
Larotrectinib is an effective treatment option for some patients with NTRK gene fusion-positive cancers. Oncology nurses are key to educating patients on dosing, administration, side effects, and precautions.


COGNITION: a prospective precision oncology trial for patients with early breast cancer at high risk following neoadjuvant chemotherapy

Abstract: Background COGNITION (Comprehensive assessment of clinical features, genomics and further molecular markers to identify patients with early breast cancer for enrolment on marker driven trials) is a diagnostic registry trial that employs genomic and transcriptomic profiling to identify biomarkers in patients with early breast cancer with a high risk for relapse after standard neoadjuvant chemotherapy (NACT) to guide genomics-driven targeted post-neoadjuvant therapy. Patients and methods At National Center for Tumor Diseases Heidelberg patients were biopsied before starting NACT, and for patients with residual tumors after NACT additional biopsy material was collected. Whole-genome/exome and transcriptome sequencing were applied on tumor and corresponding blood samples. Results In the pilot phase 255 patients were enrolled, among which 213 were assessable: thereof 48.8% were identified to be at a high risk for relapse following NACT; 86.4% of 81 patients discussed in the molecular tumor board were eligible for a targeted therapy within the interventional multiarm phase II trial COGNITION-GUIDE (Genomics-guided targeted post neoadjuvant therapy in patients with early breast cancer) starting enrolment in Q4/2022. An in-depth longitudinal analysis at baseline and in residual tumor tissue of 16 patients revealed some cases with clonal evolution but largely stable genetic alterations, suggesting restricted selective pressure of broad-acting cytotoxic neoadjuvant chemotherapies. Conclusions While most precision oncology initiatives focus on metastatic disease, the presented concept offers the opportunity to empower novel therapy options for patients with high-risk early breast cancer in the post-neoadjuvant setting within a biomarker-driven trial and provides the basis to test the value of precision oncology in a curative setting with the overarching goal to increase cure rates.


Comparison of Outcomes Between Therapeutic Combinations Based on Immune Checkpoint Inhibitors or Tyrosine Kinase Inhibitor Monotherapy for First-Line Therapy of Patients with Advanced Renal Cell Carcinoma Outside of Clinical Trials: A Real-World Retrospective Multi-Institutional Study


Operational complexity versus design efficiency: challenges of implementing a phase IIa multiple parallel cohort targeted treatment platform trial in advanced breast cancer

Abstract: Background Platform trial designs are used increasingly in cancer clinical research and are considered an efficient model for evaluating multiple compounds within a single disease or disease subtype. However, these trial designs can be challenging to operationalise. The use of platform trials in oncology clinical research has increased considerably in recent years as advances in molecular biology enable molecularly defined stratification of patient populations and targeted therapy evaluation. Whereas multiple separate trials may be deemed infeasible, platform designs allow efficient, parallel evaluation of multiple targeted therapies in relatively small biologically defined patient sub-populations with the promise of increased molecular screening efficiency and reduced time for drug evaluation. Whilst the theoretical efficiencies are widely reported, the operational challenges associated with these designs (complexity, cost, regulatory, resource) are not always well understood. Main In this commentary, we describe our practical experience of the implementation and delivery of the UK plasmaMATCH trial, a platform trial in advanced breast cancer, comprising an integrated screening component and multiple parallel downstream mutation-directed therapeutic cohorts. plasmaMATCH reported its primary results within 3 years of opening to recruitment. We reflect on the operational challenges encountered and share lessons learnt to inform the successful conduct of future trials. Key to the success of the plasmaMATCH trial was well co-ordinated stakeholder engagement by an experienced clinical trials unit with expert methodology and trial management expertise, a federated model of clinical leadership, a well-written protocol integrating screening and treatment components and including justification for the chosen structure and intentions for future adaptions, and an integrated funding model with streamlined contractual arrangements across multiple partners. Findings based on our practical experience include the importance of early engagement with the regulators and consideration of a flexible resource infrastructure to allow adequate resource allocation to support concurrent trial activities as adaptions are implemented in parallel to the continued management of patient safety and data quality of the ongoing trial cohorts. Conclusion Platform trial designs allow the efficient reporting of multiple treatment cohorts. Operational challenges can be overcome through multidisciplinary engagement, streamlined contracting processes, rationalised protocol and database design and appropriate resourcing.


Alliance A031902 (CASPAR): A randomized, phase (ph) 3 trial of enzalutamide with rucaparib/placebo as novel therapy in first-line metastatic castration-resistant prostate cancer (mCRPC).

Abstract: TPS194 Background: Despite a growing number of treatment options for first line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Androgen receptor (AR) signaling inhibition increases genomic instability with double-strand DNA breaks & co-inhibition of AR & PARP induces synthetic lethality in multiple preclinical models. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy as demonstrated in a ph 2 clinical trial of abiraterone & olaparib where this combination improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with abiraterone alone. A ph 1b trial has since shown that enzalutamide plus rucaparib has acceptable safety profile & no significant drug-drug interactions (S-DDI). Methods: CASPAR/A031902 (NCT04455750) is a ph 3 study in which 984 pts will be randomized 1:1 to enzalutamide plus rucaparib or placebo. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). Treatment will be continued until disease progression & crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or nonmeasurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, & no medications with S-DDI with enzalutamide/rucaparib. Hierarchical co-primary endpoints are rPFS & overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 & 21 months in control & combination arms, respectively) & 80% power to detect an HR of 0.80 in OS (median OS of 32 & 40 months, respectively). Key secondary endpoints are rPFS & OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; & differences in adverse events & quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF) & EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA-based testing for alterations in HRR genes. Enrollment to CASPAR began in July 2021 & the study is available for participation to all US-NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180888; Clovis Oncology; http://acknowledgments.alliancefound.org Clinical trial information: NCT04455750.


Translating the theranostic concept to neuro-oncology: disrupting barriers.

Abstract: Theranostics integrate molecular imaging and targeted radionuclide therapy for personalised cancer therapy. Theranostic treatments have shown meaningful efficacy in randomised clinical trials and are approved for clinical use in prostate cancer and neuroendocrine tumours. Brain tumours represent an unmet clinical need and theranostics might offer effective treatment options, although specific issues need to be considered for clinical development. In this Policy Review, we discuss opportunities and challenges of developing targeted radionuclide therapies for the treatment of brain tumours including glioma, meningioma, and brain metastasis. The rational choice of molecular treatment targets is highlighted, including the potential relevance of different types of targeted radionuclide therapeutics, and the role of the blood-brain barrier and blood-tumour barrier. Furthermore, we discuss considerations for effective clinical trial design and conduct, as well as logistical and regulatory challenges for implementation of radionuclide therapies into neuro-oncological practice. Rational development will foster successful translation of the theranostic concept to brain tumours.


Veterans affairs seamless phase II/III randomized trial of standard systemic therapy with or without PET-directed local therapy for oligorecurrent prostate cancer (VA STARPORT).

Abstract: TPS203 Background: Two diverging paradigms have been studied in recent years to improve the survival of men with recurrent metastatic prostate cancer (PCa). First, multiple recent phase II randomized trials have demonstrated improved long-term progression-free survival (PFS) with metastasis-directed therapy (MDT) in men with oligorecurrent PCa in the absence of systemic therapy. Yet, most patients receiving MDT for oligorecurrent PCa develop progression in new areas, arguing that systemic therapy is needed to treat occult metastases. The second approach that has recently been studied is whether escalating systemic therapy by adding novel androgen receptor axis targeted agents or chemotherapy improves outcomes in men with metastatic PCa. Multiple phase III randomized trials demonstrate that enhancing hormonal therapy with these therapeutic agents improves progression-free survival (PFS) and overall survival. Therefore, these agents have been integrated into today’s standard systemic therapy (SST) for metastatic recurrence, and SST is the current NCCN guidelines standard of care for recurrent metastatic PCa. The primary goal of our study is to determine if adding PET-directed local therapy (PDLT) to SST improves disease control compared to SST alone in Veterans with oligorecurrent PCa. Methods: VA STARPORT is a phase II/III randomized trial open at 16 VA medical centers comparing SST with or without PDLT in Veterans with oligorecurrent PCa. Key eligibility criteria include prior localized PCa with biochemical recurrence after initial curative-intent local therapy and workup including any FDA-approved PCa PET/CT that reveals oligorecurrence in 1-5 metastatic lesions. The primary endpoint is castration-resistant prostate cancer-free survival (CRPC-free survival). Secondary endpoints include radiographic PFS, clinical PFS, freedom from index lesion progression, toxicity, quality of life, and prostate cancer-specific and overall survival. SST is delivered with an intent for indefinite SST using any NCCN guideline-concordant regimen in both arms. PDLT (Arm 2) consists of surgery or radiation to metastases and any present prostate/prostate bed local recurrence. Metastasis-directed radiation can consist of stereotactic body radiotherapy or elective nodal radiotherapy per clinician discretion from dose/fractionation options defined in the protocol. All participants undergo somatic tumor sequencing using the VA National Precision Oncology Program. Germline sequencing and tumor banking in a separate biorepository study is recommended. Assuming a hazard ratio of 0.60 for SST + PDLT vs SST, two-sided alpha = 0.05 and 90% power, a total of 464 participants will be randomized to generate 166 primary events (CRPC-free survival) by the end of the 48-month active study phase. The study began enrollment in August 2021. Clinical trial information: NCT04787744.


Advancing therapy for osteosarcoma


γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial.

Abstract: Background Gamma secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance anti-tumor activity of BCMA CAR T cells in preclinical models. We report results from a clinical trial of 18 patients with relapsed/refractory multiple myeloma (MM) combining escalating doses of a BCMA-targeted therapy with a GSI. Methods Eligible patients were ≥ 18 years old, had relapsed/refractory MM, prior autologous stem cell transplant or persistent disease after > 4 cycles of induction therapy, ECOG ≤ 2, and could have received prior BCMA targeted therapy. The primary endpoints were to evaluate the safety and recommended phase 2 dose (RP2D) of BCMA CAR T cells in combination with crenigacestat, an oral GSI. To assess the impact of the GSI on bone marrow plasma cell BCMA surface density, patients received GSI during a pre-treatment “run-in” consisting of three doses administered 48 hours apart. BCMA CAR T cells were infused at a starting dose of 50 × 106 CAR+ cells, in combination with the GSI dosed three times weekly for up to 9 doses. The trial is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. Findings Eighteen patients with MM were treated from July 11, 2018 to April 14, 2021, with a median follow up of 36 months (95% CI, 26 months to not reached). Among the 10 females (56%) and 8 males (44%), 7 had prior treatment with a BCMA targeted agent. Three oral doses of crenigacestat during the “run-in” resulted in a median 12.2-times increase in BCMA density, (range, 3.18 – 156.58, Interquartile range ([IQR] 9.83 to 30.51-times). The most common non-hematologic AEs ≥ grade 3 were hypophosphatemia in 14 (78%), fatigue in 11(61%), hypocalcemia in 9 (50%), and hypertension in 7 (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Patients were treated at doses up to BCMA CAR 450 × 106 CAR+ cells and the RP2D was not reached. Interpretation Combining a GSI with BCMA CAR T cells is safe, and crenigacestat increases target antigen density. Deep responses were observed amongst heavily pre-treated BCMA exposed and naïve MM patients. Further study of GSIs given with BCMA targeted therapeutics is warranted in clinical trials. This trial was funded by Juno Therapeutics, a Bristol Myers Squibb Company.


Statistical operating characteristics of current early phase dose finding designs with toxicity and efficacy in oncology

Abstract: ABSTRACT Traditional phase I dose finding cancer clinical trial designs aim to determine the maximum tolerated dose (MTD) of the investigational cytotoxic agent based on a single toxicity outcome, assuming a monotone dose-response relationship. However, this assumption might not always hold for newly emerging therapies such as immuno-oncology therapies and molecularly targeted therapies, making conventional dose finding trial designs based on toxicity no longer appropriate. To tackle this issue, numerous early-phase dose finding clinical trial designs have been developed to identify the optimal biological dose (OBD), which takes both toxicity and efficacy outcomes into account. In this article, we review the current model-assisted dose finding designs, BOIN-ET, BOIN12, UBI, TEPI-2, PRINTE, STEIN, and uTPI to identify the OBD and compare their operating characteristics. Extensive simulation studies and a case study using a CAR T-cell therapy phase I trial have been conducted to compare the performance of the aforementioned designs under different possible dose-response relationship scenarios. The simulation results demonstrate that the performance of different designs varies depending on the particular dose-response relationship and the specific metric considered. Based on our simulation results and practical considerations, STEIN, PRINTE, and BOIN12 outperform the other designs from different perspectives.


Genomic profiling of NSCLC tumors with the TruSight oncology 500 assay provides broad coverage of clinically actionable genomic alterations and detection of known and novel associations between genomic alterations, TMB, and PD-L1

Abstract: Introduction Matching patients to an effective targeted therapy or immunotherapy is a challenge for advanced and metastatic non-small cell lung cancer (NSCLC), especially when relying on assays that test one marker at a time. Unlike traditional single marker tests, comprehensive genomic profiling (CGP) can simultaneously assess NSCLC tumors for hundreds of genomic biomarkers and markers for immunotherapy response, leading to quicker and more precise matches to therapeutics. Methods In this study, we performed CGP on 7,606 patients with advanced or metastatic NSCLC using the Illumina TruSight Oncology 500 (TSO 500) CGP assay to show its coverage and utility in detecting known and novel features of NSCLC. Results Testing revealed distinct genomic profiles of lung adenocarcinoma and squamous cell carcinomas and detected variants with a current targeted therapy or clinical trial in >72% of patient tumors. Known associations between genomic alterations and immunotherapy markers were observed including significantly lower TMB levels in tumors with therapy-associated alterations and significantly higher PD-L1 levels in tumors with ALK, MET, BRAF, or ROS1 driver mutations. Co-occurrence analysis followed by network analysis with gene module detection revealed known and novel co-occurrences between genomic alterations. Further, certain modules of genes with co-occurring genomic alterations had dose-dependent relationships with histology and increasing or decreasing levels of PD-L1 and TMB, suggesting a complex relationship between PD-L1, TMB, and genomic alterations in these gene modules. Discussion This study is the largest clinical study to date utilizing the TSO 500. It provides an opportunity to further characterize the landscape of NSCLC using this newer technology and show its clinical utility in detecting known and novel facets of NSCLC to inform treatment decision-making.


Regulatory implications of ctDNA in immuno-oncology for solid tumors

Abstract: In the era of precision oncology, use of circulating tumor DNA (ctDNA) is emerging as a minimally invasive approach for the diagnosis and management of patients with cancer and as an enrichment tool in clinical trials. In recent years, the US Food and Drug Administration has approved multiple ctDNA-based companion diagnostic assays for the safe and effective use of targeted therapies and ctDNA-based assays are also being developed for use with immuno-oncology-based therapies. For early-stage solid tumor cancers, ctDNA may be particularly important to detect molecular residual disease (MRD) to support early implementation of adjuvant or escalated therapy to prevent development of metastatic disease. Clinical trials are also increasingly using ctDNA MRD for patient selection and stratification, with an ultimate goal of improving trial efficiency through use of an enriched patient population. Standardization and harmonization of ctDNA assays and methodologies, along with further clinical validation of ctDNA as a prognostic and predictive biomarker, are necessary before ctDNA may be considered as an efficacy-response biomarker to support regulatory decision making.


Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600–Mutant Unresectable or Metastatic Melanoma

Abstract: PURPOSE Preclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma. METHODS Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692). RESULTS At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm. CONCLUSION The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations. Primary analysis of COMBI-i, a phase 3 trial of PD-1 + BRAF + MEK inhibition in BRAF-mutant melanoma.


Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study.

Abstract:
BACKGROUND
Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.

METHODS
PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/m2 and intravenous cyclophosphamide 300 mg/m2 daily for 3 days) followed 2-7 days later by two sequential lisocabtagene maraleucel infusions (equal target doses of CD8+ and CD4+ CAR+ T cells for a total target dose of 100 × 106 CAR+ T cells). The primary endpoint was the overall response rate and was assessed in all patients who received lisocabtagene maraleucel and had confirmed PET-positive disease before lisocabtagene maraleucel administration based on an independent review committee according to the Lugano 2014 criteria. Safety was assessed in all patients who received lisocabtagene maraleucel. Patient follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT03483103.

FINDINGS
Between July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p<0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.

INTERPRETATION
These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.

FUNDING
Juno Therapeutics, a Bristol-Myers Squibb company.


Preoperative and Postoperative Systemic Therapy for Operable Non-Small-Cell Lung Cancer.

Abstract: Cisplatin-based adjuvant chemotherapy remains the standard of care for patients with resected stage II or III non-small-cell lung cancer. However, biomarker-informed clinical trials are starting to push the management of early-stage lung cancer beyond cytotoxic chemotherapy. This review explores recent and ongoing studies focused on improving cytotoxic chemotherapy and incorporating targeted and immunotherapies in the management of early-stage, resectable lung cancer. Adjuvant osimertinib for patients with EGFR-mutant tumors, preoperative chemoimmunotherapy, and adjuvant immunotherapy could improve outcomes for selected patients with resectable lung cancer, and ongoing or planned studies leveraging biomarkers, immunotherapy, and targeted therapy may further improve survival. We also discuss the unique barriers associated with clinical trials of early-stage lung cancer and the need for innovative trial designs to overcome these challenges.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology


Oncolytic viral therapy engenders a clinical response in a recurrent ovarian cancer patient

Abstract: Platinum-resistant ovarian cancer frequently develops in response to multiple lines of chemotherapy, whereupon the disease becomes relatively intractable and clinical recourse is limited. We document a 58-year-old, advanced-stage, platinum-resistant ovarian cancer patient who previously failed numerous cytotoxic and targeted therapy regimens. She was referred to our gynecologic oncology service with a California (CA)-125 of 3194 U/mL and underwent a modified vaccinia virus coinciding with an Institutional Review Board-approved clinical trial. Following the oncolytic therapy and cycle 8 chemotherapy, the patient’s CA-125 declined to 440 U/mL; a computerized tomography scan of the abdomen and pelvis revealed a partial response to therapy. The favorable clinical benefit encountered in our case study indicates that the combination of oncolytic viral therapy and chemotherapy should be considered as a therapeutic option for heavily pretreated ovarian patients.


P06.04.A FIRST IN HUMAN - TARGETING ANDROGEN RECEPTOR FOR GLIOBLASTOMA THERAPY

Abstract:
 Glioblastoma represents a significant therapeutic challenge due to its aggressive nature, necessitating the development of effective targeted therapies. In a pivotal study, the amplification of the androgen receptor in 56% of glioblastomas was observed, shedding light on its therapeutic potential. Through extensive research, our team demonstrated the efficacy of the androgen receptor antagonist, enzalutamide (Xtandi), in prolonging lifespan in a mouse model of human glioblastoma. Collaborating with the Cyclotron and PET/CT teams, we established [18F]-FDHT PET/CT imaging, facilitating real-time detection of androgen receptor expression within brain tumors and enabling precise patient selection for targeted therapy.

 To proceed with a clinical trial, we conducted several steps. Initially, we examined the pharmacokinetics of enzalutamide and temozolomide, both as monotherapy and in combination, over multiple time points up to 96 hours, analyzing plasma and brain samples by LC-MS/MS. Additionally, we assessed the efficacy of PET/CT imaging for therapy response monitoring. After confirming androgen receptor expression via PET scan, patients underwent a 10-day regimen of escalating doses of the androgen antagonist Xtandi, administered daily, followed by a second PET scan.

 In the pharmacokinetic analysis, we found that the half-life (t1/2) of enzalutamide remained consistent in both plasma and brain tissue when combined with temozolomide, compared to monotherapy. Notably, the t1/2 of temozolomide increased significantly when administered concurrently, rising from 1.8 to 4.45 in plasma and from 0.88 to 7.25 in brain tissue, respectively. These results informed the clinical trial protocol design. Regarding the PET/CT study, the outcomes were promising: two potential responders identified through imaging received either 40 or 80 mg of Xtandi. The patient who received 80 mg exhibited a significant reduction in tracer uptake after ten days of treatment, accompanied by tumor shrinkage and tangible improvements in mobility and quality of life, highlighting the transformative potential of our approach.

 Encouraged by these results, we initiated a clinical trial to determine the safety and tolerability of Enzalutamide in conjunction with radiotherapy (RT) and temozolomide (TMZ), to assess clinical response using Response Assessment in Neuro-Oncology (RANO) criteria and to characterize the pharmacokinetics of Enzalutamide combined with TMZ. We have recently enrolled two patients for this study, and eagerly anticipate presenting the results of these participants, along with potentially others, during the forthcoming meeting. With the potential to rapidly translate these findings into clinical practice, our fast-track trial represents a beacon of hope for Glioblastoma patients worldwide.


Synthetic lethality-mediated precision oncology via the tumor transcriptome

Abstract: Summary Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here we introduce SELECT (SynthEtic LEthality and rescue-mediated precision onCology via the Transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients’ response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.


Erdafitinb in patients with FGFR-altered tumors: Results from the NCI-COG Pediatric MATCH trial arm B (APEC1621B).

Abstract: 10007 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients aged 1-21 years with relapsed or refractory solid tumors, CNS tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations in their tumor. Arm B (APEC1621B) evaluated the orally bioavailable FGFR inhibitor erdafitinib in patients whose tumors harbored activating alterations in FGFR 1/2/3/4. Methods: Patients received oral erdafitinib 4.7 mg/m2/dose (Max dose: 8 mg) daily for 28-day cycles until disease progression or drug related dose limiting toxicity (Max 26 cycles). Disease assessments were performed every 2-3 cycles. The primary endpoint was objective response rate; secondary endpoints included progression free survival (PFS). Results: A total of 20 evaluable patients (median age: 15 yrs) were enrolled from June 2018 to July 2022 in this first study of erdafitinib in pediatric patients. The most common diagnosis (n = 17) was glioma or glioneuronal tumor (11 low grade and 6 high grade). Three patients had non-CNS solid tumors (1 each with neuroblastoma, osteosarcoma, and rhabdomyosarcoma). FGFR alterations detected consisted of activating hotspot mutations in FGFR1 (n = 16), FGFR2 (n = 1), FGFR4 (n = 1), and FGFR1 fusions (n = 2; FGFR1: TACC1, FGFR1: TACC3). Partial responses were confirmed by central review in 2/20 patients (10%, 90%CI: 3.4%, 26.2%), both with low grade gliomas or glioneuronal tumors (LGG, LGGNT) and FGFR1 hotspot mutations (K687E and N577K). A best response of stable disease (SD) was observed in 6 additional patients with gliomas with a median duration of SD of 6.5 cycles. Six-month PFS was 45% (95% CI: 23.1%, 64.7%) and six-month OS was 89.7% (95%CI: 64.8%, 97.3%). Treatment related adverse events included those previously reported with FGFR inhibitors including hyperphosphatemia and nail changes or infections. Grade 1 vision changes were also reported. There was one Grade 3 spinal cord compression and one Grade 4 intracranial hemorrhage. Conclusions: Erdafitinib was generally well tolerated in this heavily pre-treated cohort of children with relapsed tumors harboring FGFR alterations. Partial responses or stable disease were observed in the majority (6/11, 54%) of patients with FGFR1-mutant low grade gliomas or glioneuronal tumors, suggesting the possible benefit of FGFR inhibitor therapy for these patients. Further studies would be necessary to more thoroughly evaluate the activity of erdafitinib for patients with other histologies and FGFR alteration types or combination approaches that include other targeted and/or cytotoxic agents. Clinical trial information: NCT03210714 .


Precision oncology medicines and the need for real world evidence acceptance in health technology assessment: Importance of patient involvement in sustainable healthcare.

Abstract: Precision oncology has made remarkable strides in improving clinical outcomes, offering hope to patients with historically difficult-to-treat, as well as rare or neglected cancers. However, despite rapid advancement, precision oncology has reached a critical juncture, where patient access to these life-saving medicines may be hampered by strict requirements by Health Technology Assessment (HTA) bodies for randomised controlled trials (RCTs) for assessing new medicines against appropriate comparator. The very nature of precision oncology-matching a tumour's unique molecular alterations to targeted therapies predicted to elicit response-can make the use of RCTs very difficult, as only a very small number of patients might qualify for a given therapy within a traditional clinical trial setting. Real-world evidence (RWE) has been accepted for regulatory decision-making but has yet to reach widespread acceptance by HTA bodies. As the oncology treatment landscape has evolved towards favouring the concept of precision oncology, there is a growing need for flexibility in the way HTA bodies evaluate new medicines. We must acknowledge that current assessment methodologies can limit access to life-changing medicines for many patients who have no alternative options and that a growing number of precision oncology medicines with proven clinical benefits in rare tumours cannot be reasonably evaluated using traditional methodologies. The objectives of this paper are to advocate a change in mindset regarding best practices in drug assessment models and to propose alternative approaches when considering indications for which RWE is the most compelling data source available.


Therapeutic potential of oncolytic viruses in the era of precision oncology

Abstract: ABSTRACT Oncolytic virus (OV) therapy has been shown to be an effective targeted cancer therapy treatment in recent years, providing an avenue of treatment that poses no damage to surrounding healthy tissues. Not only do OVs cause direct oncolysis, but they also amplify both innate and adaptive immune responses generating long-term anti-tumour immunity. Genetically engineered OVs have become the common promising strategy to enhance anti-tumour immunity, safety, and efficacy as well as targeted delivery. The studies of various OVs have been accomplished through phase I-III clinical trial studies. In addition, the uses of carrier platforms of organic materials such as polymer chains, liposomes, hydrogels, and cell carriers have played a vital role in the potentially targeted delivery of OVs. The mechanism, rational design, recent clinical trials, applications, and the development of targeted delivery platforms of OVs will be discussed in this review.


Design of Phase II Oncology Trials Evaluating Combinations of Experimental Agents.

Abstract: We consider the design of phase II trials evaluating combinations of experimental therapies. In the modern era, many immunotherapy and targeted therapy regimens are being developed as combination regimens, including combinations consisting only of experimental agents. In some clinical/drug development scenarios, it may be difficult to isolate the effect of the individual agents making up a combination of this type, which makes the evaluation of the combination challenging. One such scenario arises when none of the agents making up the experimental combination have demonstrated single-agent activity in the clinical setting of interest. One solution to this problem is to employ a randomized comparative trial in which the combination of interest is compared with one or both of its component agents, but because all arms in such a trial would be experimental, some modifications to more traditional randomized comparative phase II trials must be made. In this manuscript, we present sensible modifications to randomized phase II trial designs that can be employed in two common drug development scenarios of this type and provide a detailed discussion of the practical aspects of designing these trials. We also include two worked examples to further illustrate how to design such a trial.

Journal of the National Cancer Institute