Efficacy of Crizotinib After Entrectinib Resistance Due to MET Polysomy in ROS1-Rearranged NSCLC: A Case Report

Resistance to ROS1 tyrosine kinase inhibitors is inevitable, but it has been unclear whether crizotinib might be effective after the development of entrectinib resistance. We here present a case of ROS1-rearranged NSCLC that responded to crizotinib after tumor progression due to MET polysomy during entrectinib treatment. This case suggests that crizotinib is an effective option for patients with MET polysomy, even after disease progression on entrectinib

RELAY, Erlotinib Plus Ramucirumab in Untreated, EGFR-Mutated, Metastatic NSCLC: Outcomes by EGFR Exon 19 Deletion Variants

Introduction: EGFR gene mutations are drivers of NSCLC. The RELAY double-blind, placebo (PBO)-controlled phase 3 study revealed superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus PBO (PBO + ERL) in patients with untreated advanced NSCLC and an EGFR-activating mutation. This exploratory analysis evaluated potential associations between EGFR exon 19 deletion (ex19del) variants and clinical outcomes. Methods: Patients (N = 449) were randomized (1:1) to RAM plus ERL or PBO plus ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations were investigated by Guardant360 next-generation sequencing. Patients with a valid baseline plasma sample and ex19del were included (RAM + ERL, n = 62; PBO + ERL, n = 72). Results: The most common ex19del variant was E746_A750del (67.2%); EGFR E746 deletions (E746del) occurred more frequently than L747 deletions (74.6% versus 25.4%, respectively). TP53 mutations were the most frequently co-occurring baseline gene alterations. With treatment arms combined, median PFS was 18.0 months versus 12.5 months for patients with uncommon (non-E746_A750del, n = 44) versus common (E746_A750del, n = 90) ex19del variants (hazard ratio [HR] = 1.657 [95% confidence interval or CI:1.044–2.630]). Median PFS was longer with RAM plus ERL versus PBO plus ERL for patients with the common (15.2 versus 9.9 mo; HR = 0.564 [95% CI: 0.344–0.926]) and E746del (15.4 versus 9.9 mo; HR = 0.587 [95% CI: 0.363–0.951]) variants. Treatment-emergent post-progression EGFR T790M rates were higher in the common versus uncommon and E746del versus L747 deletion subgroups. Conclusions: RAM plus ERL provides benefit and improves treatment outcomes for patients with metastatic NSCLC with EGFR ex19del variants

Pembrolizumab Plus Amrubicin in Patients With Relapsed SCLC: Multi-Institutional, Single-Arm Phase 2 Study

Introduction: In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods: Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1–3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results: Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%–72.2%). Median PFS was 4.0 months (95% CI: 2.8–7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3–21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions: Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable

Phase 2 Study of YS110, a Recombinant Humanized Anti-CD26 Monoclonal Antibody, in Japanese Patients With Advanced Malignant Pleural Mesothelioma

Introduction: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study. Methods: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest). Results: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab—groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths. Conclusions: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated

Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Untreated Metastatic EGFR-Mutated NSCLC: RELAY Japanese Subset

Introduction: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46–0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. Methods: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. Results: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431–0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424–1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317–0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). Conclusions: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression