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Background: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study., Methods: In a randomized phase 3 trial, we evaluated the efficacy and safety of first-line selpercatinib as compared with control treatment that consisted of platinum-based chemotherapy with or without pembrolizumab at the investigator's discretion. The primary end point was progression-free survival assessed by blinded independent central review in both the intention-to-treat-pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were assigned to the control group) and the overall intention-to-treat population. Crossover from the control group to the selpercatinib group was allowed if disease progression as assessed by blinded independent central review occurred during receipt of control treatment., Results: In total, 212 patients underwent randomization in the intention-to-treat-pembrolizumab population. At the time of the preplanned interim efficacy analysis, median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001). The percentage of patients with an objective response was 84% (95% CI, 76 to 90) with selpercatinib and 65% (95% CI, 54 to 75) with control treatment. The cause-specific hazard ratio for the time to progression affecting the central nervous system was 0.28 (95% CI, 0.12 to 0.68). Efficacy results in the overall intention-to-treat population (261 patients) were similar to those in the intention-to-treat-pembrolizumab population. The adverse events that occurred with selpercatinib and control treatment were consistent with those previously reported., Conclusions: Treatment with selpercatinib led to significantly longer progression-free survival than platinum-based chemotherapy with or without pembrolizumab among patients with advanced RET fusion-positive NSCLC. (Funded by Eli Lilly and others; ClinicalTrials.gov number, NCT04194944.)., (Copyright © 2023 Massachusetts Medical Society.)

Pembrolizumab plus chemotherapy is currently used in the first-line treatment of advanced non-small-cell lung cancer without EGFR mutations or ALK rearrangements, regardless of PD-L1 expression status. A study comparing chemotherapy plus pembrolizumab versus pembrolizumab alone has never been performed in patients with PD-L1 ≥50%. The aim of this trial is to perform such a comparison as first-line treatment in patients not eligible for locally advanced treatment who have expression of PD-L1 on ≥50% of tumor cells. The expected results are a reduction in the risk of early progression. A higher objective tumor response is also expected with the combination of chemotherapy and pembrolizumab compared with pembrolizumab alone. The study will allow a direct comparison of the proportion of patients who derive long-term benefit from the treatment. Clinical trial number: EudraCT (2020-002626-86); ClinicalTrials.gov (NCT04547504).

Selpercatinib, a novel, highly selective and potent, inhibitor of RET , demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive RET fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic RET fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. Clinical trial registration: NCT04194944 (ClinicalTrials.gov).

Purpose: In REVEL, patients with advanced non-small-cell lung cancer (aNSCLC) and patients with increased tumor aggressiveness (rapid disease progression (RDP), platinum-refractory disease (PRD), and high symptom burden (HSB)) benefited from second-line treatment with ramucirumab plus docetaxel over placebo plus docetaxel. This post hoc analysis describes healthcare resource utilization (HCRU) associated with the treatment., Methods: aNSCLC patients who had progressed during or after first-line platinum-based chemotherapy were randomized to receive docetaxel and either ramucirumab or placebo until disease progression, unacceptable toxicity, withdrawal, or death. HCRU included hospitalizations, transfusions, and concomitant medications. Categorical variables (counts and percentages) were compared using Fisher's exact test. Continuous variables (mean, standard deviation (SD), median, minimum, and maximum) were compared using the Wilcoxon rank sum test., Results: Patient characteristics were largely similar between treatment arms. Within the intent-to-treat (ITT) population (n = 1253), the mean treatment duration was 19.7 and 16.9 weeks in the ramucirumab and control arms, respectively; 51.0% versus 54.9% of patients received subsequent anticancer therapy, respectively. Hospitalization rates were 41.9% versus 42.6% (p = 0.863), mean length of hospital stay was 14.5 days versus 11.3 days (p = 0.066), transfusion rates were 9.9% versus 12.3% (p = 0.206), and use of granulocyte colony-stimulating factors was 41.8% versus 36.6% (p = 0.063), respectively. No significant difference was observed in HCRU between treatment arms in both ITT population and in aggressive disease subgroups including RDP (n = 209), PRD (n = 360), and HSB (n = 497)., Conclusion: In REVEL, the addition of ramucirumab to docetaxel did not increase HCRU among patients with aggressive aNSCLC disease. These results may help inform economic evaluation of treatment for patients with aNSCLC.

Introduction: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease. Front-line therapy may affect responses to subsequent treatment regimens, thus influencing second-line therapy decision making. In the randomised phase 3 REVEL study, second-line ramucirumab plus docetaxel (ram+doc) versus docetaxel (doc) improved survival of patients with metastatic NSCLC. We explore efficacy, safety and quality-of-life (QoL) in REVEL based on front-line therapy., Methods: Patients were grouped by specific front-line therapy received. Overall survival (OS), progression-free survival (PFS), objective response rate, safety and QoL were assessed descriptively. Kaplan-Meier estimation and Cox proportional hazards modelling were used; frequencies reported in percentages., Results: Baseline characteristics of 1253 patients were generally well balanced between treatment arms within each front-line therapy subgroup. For patients with non-squamous disease (n=912), induction therapies included platinum-based chemotherapy plus a taxane (n=227; 25%) or pemetrexed (n=449; 49%), with (n=172; 19%) or without bevacizumab. For patients with squamous disease (n=328), induction therapies included platinum-based chemotherapy plus gemcitabine (n=176; 54%) or a taxane (n=69; 21%). A highly selected subgroup (n=127; 14%) received pemetrexed continuation maintenance therapy. Ram+doc improved median OS and PFS versus doc across front-line therapy subgroups, as reflected by HRs ranging from 0.78 to 0.91 and 0.66 to 0.92, respectively, similar to results in the overall intention-to-treat cohort (HRs: 0.86 and 0.76, respectively). High-grade treatment-emergent adverse events of special interest (including neutropenia, febrile neutropenia, leucopenia and hypertension) were generally higher in ram+doc-treated patients relative to doc-treated patients regardless of front-line therapy. No clear differences in safety or QoL were seen across front-line therapy subgroups; outcomes were consistent with those reported in the overall intention-to-treat cohort., Conclusions: Results of this exploratory analysis suggest that second-line ram+doc may be effective regardless of prior treatment with platinum-based chemotherapy plus a taxane, pemetrexed, gemcitabine or bevacizumab. Overall, ram+doc is clinically beneficial across a wide range of patients with metastatic NSCLC who have progressed after various front-line therapies., Trial Registration Number: NCT01168973., Competing Interests: Competing interests: The following authors declared conflicts of interests. GCC, AHZ, ABO, PL, KW, and VJS are full-time employees and stockowners of Eli Lilly and Company. EA is a former employee and stockowner of Eli Lilly and Company. EBG has received honoraria from Dracen and EMD Serono, and his institution has received research funding from AstraZeneca, Bristol Myers Squibb, Merck, Eli Lilly and Company, Novartis, Genentech, Dynavax, Iovance, Mirati, and Neon. GVS has received honoraria from Eli Lilly and Company, AstraZeneca, Clovis Oncology, Regeneron, Novartis, Merck Sharp and Dohme, Pfizer, and Roche and has served on the speaker’s bureaus of Eli Lilly and Company, AstraZeneca, Merck Sharp and Dohme, and Novartis. MR has received honoraria for lectures from and functions in an advisory/consulting role for Eli Lilly and Company, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Hoffman-La Roche, Merck, Novartis, and Pfizer. MT has received Advisory Board honoraria from AbbVie, Bristol Myers Squibb, Boehringer, Celgene, Eli Lilly and Company, Merck Sharp and Dohme, Novartis, Roche, Takeda; speaker’s honoraria from Eli Lilly and Company, Merck Sharp and Dohme, Takeda; research funding from AstraZeneca, Bristol Myers Squibb, Celgene, Roche; and travel grants from Bristol Myers Squibb, Boehringer, Merck Sharp and Dohme, and Novartis. HK has received reimbursement for meeting expenses and/or has functioned in an advisory/consultancy role for Eli Lilly and Company, Genesis Pharma, GlaxoSmithKline, Merck, Novartis, Pfizer, and Roche and has received reimbursement for meeting expenses from Enorasis. J-HK serves in an advisory/consultancy role for and his institution has received grant funding for clinical trials from Eli Lilly and Company, including during the conduct of this study, and from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, and Roche. OTB has received honoraria from Eli Lilly and Company, AstraZeneca, Boehringer Ingelheim (for research funding and advisory/consultancy role), GlaxoSmithKline (for research funding), Merck (for advisory/consultancy role), Novartis, Pfizer, and Roche (for research funding). MP has received honoraria for speaking, advisory and consultancy roles for Eli Lilly and Company., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Objectives: The REVEL study demonstrated improved efficacy with ramucirumab plus docetaxel versus placebo plus docetaxel for previously treated advanced/metastatic non-small-cell lung cancer (NSCLC) without further detriment to patient quality of life, symptoms, or functioning. This post hoc analysis explored the association between baseline Lung Cancer Symptom Scale (LCSS) Average Symptom Burden Index (ASBI) and efficacy., Materials and Methods: Baseline ASBI scores were the average of the 6 LCSS symptom components. Low and high symptom burden (LSB ≤ median, HSB > median) were analyzed across and by treatment arms for effects on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) using the Kaplan-Meier method and Cox proportional hazards model., Results: Baseline LCSS compliance was approximately 78% in both REVEL treatment arms. Patients with LSB versus HSB had fewer poor prognostic factors. The HSB patient population significantly overlapped with previously identified aggressive disease subgroups (rapidly progressing disease or refractory to first-line treatment). Patients with LSB versus HSB had significantly improved OS (P < 0.0001), PFS (P < 0.0001), and ORR (P = 0.0003) regardless of treatment, with superior ORR and PFS but not OS in the ramucirumab plus docetaxel arm. Patients with HSB treated with ramucirumab plus docetaxel versus docetaxel had improved OS (median, 7.39 vs. 5.95 months; HR 0.749 [95% CI 0.610-0.920]; P = 0.0308), PFS (median, 4.01 vs. 2.63 months; HR 0.749 [0.619-0.907]; P = 0.0202), and ORR (18% vs. 11%; P = 0.0458). Of patients with rapidly progressing disease, 57% (92/162) also had HSB., Conclusions: Baseline ASBI may be an independent prognostic factor in this large second-line cohort of patients with advanced NSCLC. The preservation of improved PFS and OS in the HSB cohort suggests that the addition of ramucirumab to docetaxel provides benefit in patients with greater symptom burden, consistent with previous data on REVEL patients with aggressive disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)