First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion–Positive NSCLC

BackgroundSelpercatinib, 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.MethodsIn 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.ResultsIn 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.ConclusionsTreatment 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.

A phase II single-arm study of induction chemotherapy with cisplatin and gemcitabine followed by concurrent cisplatin and gemcitabine with thoracic radiation for unresectable locally advanced non-small cell lung cancer

Objectives: The aim of this study was to evaluate the efficacy and tolerability of the combination of cisplatin–gemcitabine with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: This was a phase II, multicenter, open-label, single-arm trial in treatment-naïve patients with stage IIIA and IIIB LA-NSCLC. After three induction cycles with gemcitabine 1250 mg/m 2 plus cisplatin 80 mg/m 2 , two concurrent chemoradiotherapy cycles with gemcitabine 300 mg/m 2 , cisplatin 80 mg/m 2 , and radiotherapy (63 Gy) were administered. The primary endpoint was response rate after induction chemotherapy followed by concurrent chemoradiotherapy. Secondary endpoints included time to progressive disease (TtPD), overall survival (OS), and safety. Results: Overall, 49 patients (median age 63.4 years; 73.5% male; Karnofsky performance status scores of 80, 85, 90, and 100 [16.3%, 2.0%, 49.0%, and 32.7%, respectively]; disease stage IIIA or IIIB 28.6% and 71.4%, respectively) were enrolled and treated. Response rate was 38.8% (95% confidence interval [CI] 25.2–53.8%). Median TtPD was 11.4 months (95% CI 9.4–12.9). Median OS was 21.8 months (95% CI 17.5–26.0), with 1- and 2-year survival rates of 70.8% and 43.7%, respectively. Overall, six patients discontinued from study treatment due to adverse events (AEs), of which two were serious AEs. The most relevant grade 3/4 AEs were neutropenia and thrombocytopenia in induction chemotherapy and chemoradiotherapy, and grade 3 events related to radiation in acute chemoradiotherapy, e.g. dysphagia, radiation pneumonitis, and radiation esophagitis. Conclusions: Induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine (300 mg/m 2 ) and cisplatin was associated with acceptable toxicity. The observed median OS time was 21.8 months. Response evaluation was difficult as in many cases it was not possible to differentiate tumor progression from local radiofibrosis

Quality of life of patients with soft tissue sarcoma treated with doxorubicin in the ANNOUNCE phase III clinical trial

Background: Patient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from trials of sarcoma patients. In this analysis, pooled PRO data are reported from patients with advanced or metastatic soft tissue sarcoma (STS) enrolled to the ANNOUNCE phase III trial of doxorubicin-based therapy. Methods: ANNOUNCE was a phase III trial that randomized 509 patients with STS to receive up to eight cycles of doxorubicin with olaratumab or placebo, followed by single-agent olaratumab or placebo. Dexrazoxane was allowed at any cycle of treatment. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30, which is scored 0–100), and Brief Pain Inventory Short Form Modified (mBPI-sf, scored from 0–10) at each treatment cycle. A descriptive analysis of the longitudinal data was conducted overall and by cumulative dose of doxorubicin received to inform the clinical care of patients with STS. Worsening on the QLQ-C30 was defined as a change of 10 points or more at any post-baseline assessment. Worsening on the mPBI-sf was defined as an increase of ≥2 points from baseline. Results: The majority of participants completed the baseline and at least one subsequent PRO assessment within the trial (n = 460, 90.4% EORTC QLQ-C30; n = 454, 89.2%, mBPI-sf). Patients with STS enrolled to the ANNOUNCE trial had clinically meaningful problems with physical function and pain before initiating doxorubicin. Overall, those with fewer symptoms or better function at baseline received higher cumulative doxorubicin dose throughout the study. At baseline, mean QLQ-C30 fatigue was 29.9 with a median time to first worsening of 0.9 months, and mean nausea/vomiting was 6.5 with 1.4 months until worsening; mean physical function was 78.3 with median time to worsening of 2.1 months and mean health status was 66.8 with median time to first worsening of 1.6 months. Median time to worsening of pain was 7.9 months. Conclusion: Patients with advanced or metastatic sarcoma reported a relatively rapid decline in PROs during doxorubicin-based treatment, with patients with poorer symptoms at baseline (specifically fatigue), subsequently receiving less doxorubicin therapy. The availability of detailed summary data from the patient perspective during doxorubicin-based treatment may inform future care of these patients and can provide a resource for the development of PRO endpoints in future trials

Final results from a Phase II study of pemetrexed and cisplatin with concurrent thoracic radiation after Pem-Cis induction in patients with unresectable locally advanced non-squamous non-small cell lung cancer (NSCLC)

n/

A phase 1b study of necitumumab in combination with abemaciclib in patients with stage IV non-small cell lung cancer

International audienceNecitumumab, an anti-EGFR antibody, and abemaciclib, a CDK4/6 inhibitor, have shown activity in patients with non-small cell lung cancer (NSCLC) and have non-overlapping toxicities. A 2-part, single-arm, multicenter, phase 1b trial was conducted to test the safety and efficacy of necitumumab plus abemaciclib in patients with advanced NSCLC who had received ≤2 lines of chemotherapy, including a platinum-based one

Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. METHODS: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. RESULTS: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). CONCLUSIONS: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible