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Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation.

ABSTRACT: LESSONS LEARNED:This study evaluating first-line crizotinib plus pembrolizumab in patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) was terminated early because increased availability of second-generation ALK inhibitors resulted in difficulty identifying and accruing eligible patients. In the small number of patients enrolled, elevated transaminases were the most common treatment-related toxicity. No other relevant toxicities were observed. Although no definitive conclusions could be drawn because of the small number of patients studied, the higher frequency of severe transaminase increases noted in this sample should be of concern if ALK inhibitor and PD-L1/PD-1 inhibitor combinations are tested in future studies. BACKGROUND:Previous research suggests single-agent crizotinib is efficacious for the treatment of anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC). METHODS:This study evaluated the safety and preliminary antitumor activity of crizotinib plus pembrolizumab as first-line therapy in patients with ALK-rearranged NSCLC. Patients were initially treated at dose level 0 (DL0) with crizotinib 250 mg twice daily and pembrolizumab 200 mg every 3?weeks (cycle duration was 3?weeks). If a dose-limiting toxicity occurred, subsequent patients were enrolled at a lower dose level (dose level -1 [DL-1]: 3?weeks of crizotinib monotherapy 250 mg twice daily, followed by crizotinib 250 mg twice daily with the addition of pembrolizumab 200 mg every 3?weeks). The primary endpoint was dose-limiting toxicity. Antitumor activity was assessed. RESULTS:Nine patients were enrolled: two at DL0, then seven at DL-1. Dose-limiting toxicities occurred in four patients (grade 3 increases in alanine aminotransferase [ALT] and aspartate aminotransferase [AST] and grade 3 fatigue at DL0; grade 3 increase in ALT and grade 3 increases in both ALT and AST at DL-1). CONCLUSION:The maximum tolerated dose was not determined because slow accrual resulted in early study termination.

SUBMITTER: Patel SP

PROVIDER: S-EPMC7356710 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation.

Patel Sandip Pravin SP Pakkala Suchita S Pennell Nathan A NA Reckamp Karen L KL Lanzalone Silvana S Polli Anna A Tarazi Jamal J Robert-Vizcarrondo Francisco F

The oncologist 20200212 7

<h4>Lessons learned</h4>This study evaluating first-line crizotinib plus pembrolizumab in patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) was terminated early because increased availability of second-generation ALK inhibitors resulted in difficulty identifying and accruing eligible patients. In the small number of patients enrolled, elevated transaminases were the most common treatment-related toxicity. No other relevant toxicities were observe ...[more]

PMID: 32048771

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Project description:PurposeThe immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti-PD-1 antibody) in unresectable HCC (uHCC).Patients and methodsIn this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase).ResultsA total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified.ConclusionLenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

Project description:LESSONS LEARNED:Ramucirumab plus pembrolizumab revealed no unexpected safety findings in patients with advanced or metastatic biliary tract cancer, which is consistent with reports of other tumor cohorts within this phase Ia/b trial.Ramucirumab plus pembrolizumab did not demonstrate an improvement in overall survival when compared with historical controls in biomarker unselected, heavily pretreated patients with advanced or metastatic biliary tract cancer.Patients with programmed death-ligand 1 (PD-L1)-positive tumors had improved overall survival compared with patients with PD-L1-negative disease. BACKGROUND:Few treatment options exist for patients with advanced biliary tract cancer (BTC) following progression on gemcitabine-cisplatin. Preclinical evidence suggests that simultaneous blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) and programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) enhances antitumor effects. We assessed the safety and efficacy of ramucirumab, an IgG1 VEGFR-2 antagonist, with pembrolizumab, an IgG4 PD-1 antagonist, in biomarker-unselected patients with previously treated advanced or metastatic BTC. METHODS:Patients had previously treated advanced or metastatic adenocarcinoma of the gallbladder, intrahepatic and extrahepatic bile ducts, or ampulla of Vater. Ramucirumab 8 mg/kg was administered intravenously on days 1 and 8 with intravenous pembrolizumab 200 mg on day 1 every 3 weeks. The primary endpoint was safety and tolerability of the combination. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS:Twenty-six patients were treated at 12 centers in five countries. Hypertension was the most common grade 3 treatment-related adverse event (TRAE), occurring in five patients. One patient experienced a grade 4 TRAE (neutropenia), and no treatment-related deaths occurred. Objective response rate was 4%. Median progression-free survival and overall survival were 1.6 months and 6.4 months, respectively. CONCLUSION:Ramucirumab-pembrolizumab showed limited clinical activity with infrequent grade 3-4 TRAEs in patients with biomarker-unselected progressive BTC.

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Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation.

Publications

Phase Ib Study of Crizotinib plus Pembrolizumab in Patients with Previously Untreated Advanced Non-Small Cell Lung Cancer with ALK Translocation.

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