Eftilagimod alpha (soluble LAG-3 protein) combined with pembrolizumab as second-line therapy for patients with metastatic head and neck squamous cell carcinoma.

PURPOSE: Eftilagimod alpha (efti), a soluble LAG-3 protein, activates antigen-presenting cells (APC) and downstream T-cells. TACTI-002 (Part C) evaluated whether combining efti with pembrolizumab led to strong anti-tumor responses in 2nd line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients, while demonstrating good tolerability. METHODS: In this multinational phase 2 trial using Simon's 2-stage design, R/M HNSCC PD-L(1)-naïve patients who had failed first-line platinum-based therapy, unselected for PD-L1, received intravenous pembrolizumab (200 mg, Q3W) combined with subcutaneous efti (30 mg Q2W for 24 weeks and Q3W thereafter). The primary endpoint was objective response rate (ORR) per iRECIST by investigator assessment. Additional endpoints included duration of response (DoR), progression free survival (PFS), overall survival (OS) and tolerability. Pharmacodynamic effects (absolute lymphocyte count [ALC] and Th1 cytokine biomarkers [IFN-gamma/CXCL-10]) were evaluated in liquid biopsies. RESULTS: Between Mar 2019 - Jan 2021, 39 patients were enrolled; 37 were evaluated for response. All patients received prior chemotherapy and 40.5% were pretreated with cetuximab. 53.1% of patients had PD-L1 CPS <20. With a median follow up of 38.8 months, ORR was 29.7%, including 13.5% complete responders. Median DoR was not reached. Rapid and sustained ALC increase was observed in patients who had an objective response. Th1 biomarkers increased sustainably after first treatment. No unexpected safety signals were observed. CONCLUSION: Efti plus pembrolizumab was safe and showed encouraging antitumor activity and pharmacodynamic effects in 2nd line HNSCC patients, thus supporting further evaluation of this combination in earlier treatment lines.

PCM4EU and PRIME-ROSE: Collaboration for implementation of precision cancer medicine in Europe.

BACKGROUND: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. PATIENTS AND METHODS: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. RESULTS: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.

A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary.

Cancers of Unknown Primary (CUP) remains a diagnostic and therapeutic challenge due to biological heterogeneity and poor responses to standard chemotherapy. Predicting tissue-of-origin (TOO) molecularly could help refine this diagnosis, with tissue acquisition barriers mitigated via liquid biopsies. However, TOO liquid biopsies are unexplored in CUP cohorts. Here we describe CUPiD, a machine learning classifier for accurate TOO predictions across 29 tumour classes using circulating cell-free DNA (cfDNA) methylation patterns. We tested CUPiD on 143 cfDNA samples from patients with 13 cancer types alongside 27 non-cancer controls, with overall sensitivity of 84.6% and TOO accuracy of 96.8%. In an additional cohort of 41 patients with CUP CUPiD predictions were made in 32/41 (78.0%) cases, with 88.5% of the predictions clinically consistent with a subsequent or suspected primary tumour diagnosis, when available (23/26 patients). Combining CUPiD with cfDNA mutation data demonstrated potential diagnosis re-classification and/or treatment change in this hard-to-treat cancer group.

Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R. METHODS: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. RESULTS: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events. CONCLUSIONS: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.).

A plain language summary of the results from the group of patients in the CHRYSALIS study with EGFR exon 20 insertion-mutated non-small-cell lung cancer who received amivantamab.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article published in the Journal of Clinical Oncology in 2021. It describes the first results from 1 group of patients in the phase 1 CHRYSALIS study with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations. This part of the CHRYSALIS study (called cohort D) investigated the bispecific antibody amivantamab (brand name RYBREVANT®) in patients with non-small-cell lung cancer (NSCLC) with an EGFR ex20ins mutation. EGFR mutations are one of the most common causes of NSCLC tumors, with EGFR ex20ins mutations being more common among people of Asian descent. Patients who took part in this study had cancer that could not be removed by surgery, and whose cancer had worsened after receiving other forms of treatment, such as chemotherapy. Typically, patients with this type of mutation are difficult to treat or do not experience treatment response with commonly used therapies that target EGFR. WHAT WERE THE RESULTS?: The CHRYSALIS study took place between May 27, 2016, and June 8, 2020, in select hospitals in the USA, Japan and South Korea. In cohort D, amivantamab showed promising results, with an overall response rate of 40%. This means that 4 of every 10 patients in CHRYSALIS cohort D had tumors that shrank or were no longer measurable. Clinical Trial Registration: NCT02609776 (the CHRYSALIS Phase I Study) (ClinicalTrials.gov).

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation.

BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).

Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib.

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

RETaliation-Tackling Rare Resistance Alterations to Osimertinib.

RET fusions occur as a rare mechanism of acquired resistance to osimertinib in patients with EGFR mutation-positive non-small cell lung cancer. Inhibiting RET alongside osimertinib shows promising clinical activity, but innovative approaches are needed to seek regulatory approvals in these rare treatment resistance settings. See related article by Rotow et al., p. 2979.

A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer.

INTRODUCTION: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. MATERIALS AND METHODS: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). RESULTS: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. CONCLUSION: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.

Olaparib and durvalumab in patients with relapsed small cell lung cancer (MEDIOLA): An open-label, multicenter, phase 1/2, basket study.

INTRODUCTION: Preclinical studies have demonstrated increased efficacy with combined DNA damage response inhibition and immune checkpoint blockade compared with either alone. We assessed olaparib in combination with durvalumab in patients with relapsed small cell lung cancer (SCLC). METHODS: Patients with previously treated limited or extensive-stage SCLC received oral olaparib 300 mg twice daily, as run-in for 4 weeks, then with durvalumab (1500 mg intravenously every 4 weeks) until disease progression. Primary endpoints were safety, tolerability, and 12-week disease control rate (DCR). Secondary endpoints included 28-week DCR, objective response rate (ORR), duration of response, progression-free survival, overall survival, change in tumor size, and programmed death-ligand 1 (PD-L1) expression subgroup analyses. RESULTS: Forty patients were enrolled and analyzed for safety; 38 were analyzed for efficacy. Eleven patients (28.9% [90% confidence interval (CI), 17.2-43.3]) had disease control at 12 weeks. ORR was 10.5% (95% CI, 2.9-24.8). Median progression-free and overall survival were 2.4 (95% CI, 0.9-3.0)months and 7.6(95% CI, 5.6-8.8)months, respectively. The most common adverse events (≥40.0%) were anemia, nausea, and fatigue. Grade ≥ 3 adverse events occurred in 32 patients (80.0%). PD-L1 levels, tumor mutational burden, and other genetic mutations were evaluated, but no significant correlations with clinical outcomes wereobserved. CONCLUSIONS: Tolerability of olaparib with durvalumab was consistent with the safety profile of each agent alone. Although the 12-week DCR did not meet the prespecified target (60%), four patients responded, and median overall survival was promising for a pretreated SCLC population. Further analyses are required to identify patients most likely to benefit from this treatment approach.

Real-World Comparative Effectiveness of First-Line Alectinib Versus Crizotinib in Patients With Advanced ALK-Positive NSCLC With or Without Baseline Central Nervous System Metastases.

Introduction: Alectinib was found to have superior efficacy to crizotinib in the phase 3 ALEX study and is a preferred initial treatment for patients with advanced ALK-positive NSCLC. To understand the efficacy of alectinib in U.S. clinical practice, we conducted a retrospective real-world comparative effectiveness analysis of first-line alectinib versus crizotinib. Methods: Adults with advanced ALK-positive NSCLC who received first-line alectinib (from December 11, 2015) or crizotinib (from January 1, 2014) were included from a real-world database. Propensity scores were applied to balance baseline characteristics. Real-world data (RWD), including real-world progression-free survival (rwPFS), real-world overall survival, real-world time to new central nervous system (CNS) metastases, and outcomes in patients with or without baseline CNS metastases were analyzed. The ALEX-like RWD cohort (filtered by ALEX laboratory eligibility criteria) was used to compare real-world comparative effectiveness with ALEX. Results: The RWD cohort comprised 364 patients (141 alectinib; 223 crizotinib); rwPFS (weighted hazard ratio [wHR] = 0.46, 95% confidence interval [CI]: 0.33-0.65) and real-world overall survival (wHR = 0.46, 95% CI: 0.31-0.69) were significantly improved with alectinib versus crizotinib. In patients with baseline brain scans, a substantial rwPFS benefit was found regardless of baseline CNS metastases. Real-world time to new CNS metastases was delayed with alectinib versus crizotinib in patients with (wHR = 0.28, 95% CI: 0.16-0.52) and without (wHR = 0.42, 95% CI: 0.24-0.76) baseline CNS metastases. The ALEX-like RWD cohort comprised 325 patients (120 alectinib; 205 crizotinib); alectinib was found to have similar rwPFS benefits with ALEX. Conclusions: Outcomes were significantly improved with first-line alectinib versus crizotinib in patients with advanced ALK-positive NSCLC in the U.S. real-world setting.

Digital ECMT Cancer Trial Matching Tool: an Open Source Research Application to Support Oncologists in the Identification of Precision Medicine Clinical Trials.

PURPOSE: Matching patients with cancer to precision medicine clinical trials on the basis of their tumor genotype has the potential to improve outcomes for patients who have exhausted standard-of-care treatment options. However, the matching process presents a substantial challenge because of the number of clinical trials available. We describe a free, open source research tool designed to extract relevant trial information to support oncologists in the matching process, and we illustrate its utility with recent case studies of patients who were matched to trials using this tool. METHODS: Trial records are sourced from ClinicalTrials.gov and indexed using natural language processing techniques, including named entity recognition, term normalization, and relationship extraction. Relationships between trials and genetic alterations are assigned scores on the basis of a rule-based system. All data are updated daily. A user interface is provided via R Shiny app. RESULTS: An instance of the trial match tool, configured for UK clinical trials, is hosted by the digital Experimental Cancer Medicine Team (see link in Data Sharing Statement). Users select the relevant cancer type and genetic alteration(s). Matching studies are ranked according to the score assigned for the selected genetic alterations. Results may be downloaded and attached to the patient's health record if desired. The tool is currently being used to support the ongoing TARGET National study, which aims to match up to 6,000 patients to early phase clinical trials. We present three case studies that exemplify relationships between genetic alterations and studies. CONCLUSION: With increasing numbers of precision medicine treatments and as comprehensive molecular profiling of tumor samples becomes more common, decision support tools are likely to become increasingly important. This work represents an important step toward the development and wider implementation of such systems.

Practical Considerations for the Use of Circulating Tumor DNA in the Treatment of Patients With Cancer: A Narrative Review.

Importance: Personalized medicine based on tumor profiling and identification of actionable genomic alterations is pivotal in cancer management. Although tissue biopsy is still preferred for diagnosis, liquid biopsy of blood-based tumor analytes, such as circulating tumor DNA, is a rapidly emerging technology for tumor profiling. Observations: This review presents a practical overview for clinicians and allied health care professionals for selection of the most appropriate liquid biopsy assay, specifically focusing on circulating tumor DNA and how it may affect patient treatment and case management across multiple tumor types. Multiple factors influence the analytical validity, clinical validity, and clinical utility of testing. This review provides recommendations and practical guidance for best practice. Current methodologies include polymerase chain reaction-based approaches and those that use next-generation sequencing (eg, capture-based profiling, whole exome, or genome sequencing). Factors that may influence utility include sensitivity and specificity, quantity of circulating tumor DNA, detection of a small vs a large panel of genes, and clonal hematopoiesis of indeterminate potential. Currently, liquid biopsy appears useful in patients unable to undergo biopsy or where mutations detected may be more representative of the predominant tumor burden than for tissue-based assays. Other potential applications may include screening, primary diagnosis, residual disease, local recurrence, therapy selection, or early therapy response and resistance monitoring. Conclusions and Relevance: This review found that liquid biopsy is increasingly being used clinically in advanced lung cancer, and ongoing research is identifying applications of circulating tumor DNA-based testing that complement tissue analysis across a broad range of clinical settings. Circulating tumor DNA technologies are advancing quickly and are demonstrating potential benefits for patients, health care practitioners, health care systems, and researchers, at many stages of the patient oncologic journey.

Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC.

Introduction: Entrectinib is an approved tyrosine kinase inhibitor (TKI) for ROS1 fusion-positive NSCLC. An updated integrated analysis of entrectinib from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials is presented, with substantially longer follow-up, more patients, and the first description of the median overall survival (OS). An exploratory analysis of entrectinib in ROS1 fusion-positive NSCLC with the central nervous system (CNS)-only progression post-crizotinib is reported. Methods: Adults with ROS1 fusion-positive, locally advanced or metastatic NSCLC who received at least one dose of entrectinib and had 12 months or longer of follow-up were included in the analysis. Co-primary end points were confirmed objective response rate (ORR) and duration of response (DoR) by blinded independent central review. The data cutoff was on August 31, 2020. Results: The efficacy-assessable population comprised 168 ROS1 TKI-naïve patients. The median survival follow-up was 29.1 months (interquartile range, 21.8-35.9). The ORR was 68% (95% confidence interval [CI]: 60.2-74.8); the median DoR was 20.5 months. The median progression-free survival (PFS) was 15.7 months and the median OS was 47.8 months. In the 25 patients with measurable baseline CNS metastases, the intracranial ORR was 80% (95% CI: 59.3-93.2), median intracranial DoR was 12.9 months, and median intracranial PFS was 8.8 months. Among 18 patients with CNS-only progression on previous crizotinib treatment, two achieved a partial response (11%) and four had stable disease (22%). In seven patients with measurable CNS disease from this cohort, the intracranial ORR was 14% (1 partial response). Conclusions: Entrectinib is active and achieves prolonged survival in ROS1 TKI-naïve patients with ROS1 fusion-positive NSCLC. Modest activity is seen in patients with CNS-only progression post-crizotinib.

Oncology patients' experiences in experimental medicine cancer trials: a qualitative study.

OBJECTIVES: The study aimed to explore patients' experiences of experimental cancer medicine (ECM) clinical trials. DESIGN: The study's design was qualitative. Two focus groups with patients were undertaken followed by semistructured interviews, to explore patients' experiences of ECM clinical trials. Interviews and focus groups were audiorecorded and transcribed verbatim. Data were analysed using thematic analysis. SETTING: A regional cancer centre (tertiary care) in North-West England. PARTICIPANTS: Twelve patients (aged 52-79) participated in one of the two focus groups and 22 patients (aged 42-83) participated in interviews. PRIMARY OUTCOME MEASURE: Patients' experiences of an ECM trial. RESULTS: Four main themes were identified from the analysis: decision making, information needs, the experience of trial participation and impact of trial participation. Subthemes are presented in the manuscript. CONCLUSION: To make fully informed decisions about trial participation, patients required the simplification of trial information and wanted more information about side effects, their response to trial treatment and the overall trial progress throughout the trial. Patients highlighted the need for improvement for the support provided to their family and friends.

Comparative effectiveness analysis between entrectinib clinical trial and crizotinib real-world data in ROS1+ NSCLC.

Aim: Generating direct comparative evidence in prospective randomized trials is difficult for rare diseases. Real-world cohorts may supplement control populations. Methods: Entrectinib-treated adults with advanced ROS1 fusion-positive NSCLC (n = 94) from Phase I/II trials (ALKA-372-001 [EudraCT2012-00148-88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]) were compared with a real-world crizotinib-treated cohort (n = 65). Primary end point, time-to-treatment discontinuation (TTD); secondary end points, PFS and OS. Results: Median (95% CI) weighted TTD: 12.9 (9.9-17.4) months for entrectinib; 8.8 (6.2-9.9) months for crizotinib (weighted hazard ratio: 0.72 [0.51-1.02]). Median OS with entrectinib was not reached, weighted median OS with crizotinib was 18.5 (15.1-19.9) months. Conclusion: Entrectinib administered in clinical trials may be associated with longer TTD than a real-world crizotinib population.

Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study.

PURPOSE: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site. METHODS: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. RESULTS: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively. CONCLUSION: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.

Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study.

PURPOSE: This study reports the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity of ceralasertib combined with carboplatin in patients with advanced solid tumors. It also examined exploratory predictive and pharmacodynamic biomarkers. PATIENTS AND METHODS: Eligible patients (n = 36) received a fixed dose of carboplatin (AUC5) with escalating doses of ceralasertib (20 mg twice daily to 60 mg once daily) in 21-day cycles. Sequential and concurrent combination dosing schedules were assessed. RESULTS: Two ceralasertib MTD dose schedules, 20 mg twice daily on days 4-13 and 40 mg once daily on days 1-2, were tolerated with carboplatin AUC5; the latter was declared the RP2D. The most common treatment-emergent adverse events (Common Terminology Criteria for Adverse Events grade ≥3) were anemia (39%), thrombocytopenia (36%), and neutropenia (25%). Dose-limiting toxicities of grade 4 thrombocytopenia (n = 2; including one grade 4 platelet count decreased) and a combination of grade 4 thrombocytopenia and grade 3 neutropenia occurred in 3 patients. Ceralasertib was quickly absorbed (tmax ∼1 hour), with a terminal plasma half-life of 8-11 hours. Upregulation of pRAD50, indicative of ataxia telangiectasia mutated (ATM) activation, was observed in tumor biopsies during ceralasertib treatment. Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed RECIST v1.1 partial responses. Eighteen of 34 (53%) response-evaluable patients had RECIST v1.1 stable disease. CONCLUSIONS: The RP2D for ceralasertib plus carboplatin was established as ceralasertib 40 mg once daily on days 1-2 administered with carboplatin AUC5 every 3 weeks, with pharmacokinetic and pharmacodynamic studies confirming pharmacodynamic modulation and preliminary evidence of antitumor activity observed.