Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: Updated results from the phase 3 COSMIC-311 trial.

BACKGROUND: At an interim analysis (median follow-up, 6.2 months; n = 187), the phase 3 COSMIC-311 trial met the primary end point of progression-free survival (PFS): cabozantinib improved PFS versus a placebo (median, not reached vs. 1.9 months; p < .0001) in patients with previously treated radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). The results from an exploratory analysis using an extended datacut are presented. METHODS: Patients 16 years old or older with RAIR-DTC who progressed on prior lenvatinib and/or sorafenib were randomized 2:1 to oral cabozantinib tablets (60 mg/day) or a placebo. Placebo patients could cross over to open-label cabozantinib upon radiographic disease progression. The objective response rate (ORR) in the first 100 randomized patients and the PFS in the intent-to-treat population, both according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent review, were the primary end points. RESULTS: At the data cutoff (February 8, 2021), 258 patients had been randomized (cabozantinib, n = 170; placebo, n = 88); the median follow-up was 10.1 months. The median PFS was 11.0 months (96% confidence interval [CI], 7.4-13.8 months) for cabozantinib and 1.9 months (96% CI, 1.9-3.7 months) for the placebo (hazard ratio, 0.22; 96% CI, 0.15-0.32; p < .0001). The ORR was 11.0% (95% CI, 6.9%-16.9%) versus 0% (95% CI, 0.0%-4.1%) (p = .0003) with one complete response with cabozantinib. Forty placebo patients crossed over to open-label cabozantinib. Grade 3/4 treatment-emergent adverse events occurred in 62% and 28% of the cabozantinib- and placebo-treated patients, respectively; the most common were hypertension (12% vs. 2%), palmar-plantar erythrodysesthesia (10% vs. 0%), and fatigue (9% vs. 0%). There were no grade 5 treatment-related events. CONCLUSIONS: At extended follow-up, cabozantinib maintained superior efficacy over a placebo in patients with previously treated RAIR-DTC with no new safety signals.

Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population. METHODS: In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice-web response system; both patients and investigators were masked to study treatment. Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first 100 randomly assigned patients (objective response rate intention-to-treat [OITT] population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients. FINDINGS: Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was 6·2 months (IQR 3·4-9·2) for the ITT population and 8·9 months (7·1-10·5) for the OITT population. An objective response in the OITT population was achieved in ten (15%; 99% CI 5·8-29·3) of 67 patients in the cabozantinib group versus 0 (0%; 0-14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5·7-not estimable [NE]) versus 1·9 months (1·8-3·6); hazard ratio 0·22 (96% CI 0·13-0·36; p<0·0001). Grade 3 or 4 adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the most frequent of which were palmar-plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11 [9%] vs 2 [3%]), and fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths. INTERPRETATION: Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care. FUNDING: Exelixis.

A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105.

RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.This article is highlighted in the In This Issue feature, p. 305.

Antitumor Activity of RXDX-105 in Multiple Cancer Types with RET Rearrangements or Mutations.

Purpose: While multikinase inhibitors with RET activity are active in RET-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations.Experimental design: The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed by in vivo tumor growth inhibition studies in cell line- and patient-derived xenograft models. Antitumor activity in patients was assessed by imaging and Response Evaluation Criteria in Solid Tumors (RECIST).Results: Biochemically, RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A-RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of CCDC6-RET-rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in CCDC6-RET, NCOA4-RET, and KIF5B-RET-containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCγ. Additionally, a patient with advanced RET-rearranged lung cancer had a rapid and sustained response to RXDX-105 in both intracranial and extracranial disease.Conclusions: These data support the inclusion of patients bearing RET alterations in ongoing and future molecularly enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types. Clin Cancer Res; 23(12); 2981-90. ©2016 AACR.

A phase I/II study of LY900003, an antisense inhibitor of protein kinase C-alpha, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer.

PURPOSE: Protein kinase C-alpha has been implicated in malignant transformation and proliferation. Based on in vivo superadditive interaction between the protein kinase C-alpha antisense oligonucleotide LY900003 (Affinitak, ISIS 3521) and cisplatin, we designed this phase I/II trial of LY900003 with cisplatin/gemcitabine. EXPERIMENTAL DESIGN: The safety of the combination, as well as potential pharmacokinetic interactions, was evaluated in the phase I portion of the trial. The phase II portion evaluated the antitumor activity of the combination in previously untreated patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). RESULTS: Seven patients received 18 cycles of the combination during the phase I portion. Dose-limiting toxicity was only observed in one of six evaluable patients (grade 3 fatigue). However, due to a relatively high frequency of thrombocytopenia, cisplatin 80 (mg/m2) and gemcitabine (1,000 mg/m2) were recommended for the phase II portion. Antitumor activity was observed in two patients (one with NSCLC and one with pancreatic carcinoma), and prolonged stabilization was observed in two others. No pharmacokinetic interactions occurred. In the phase II portion, 55 NSCLC patients received the combination at two gemcitabine doses [1,000 mg/m2, n=44 (original cohort); 1,250 mg/m2, n=11 (expanded cohort)]. Fourteen of 39 evaluable patients in the original cohort had a response rate (1 complete response and 13 partial responses; response, 36%), whereas 2 of 9 evaluable patients in the expanded cohort experienced partial response (combined response rate, 33%). The median time to treatment failure was 3.9 months, whereas the median time response to progression for the 48 patients with evaluable response was 4.4 months (confidence interval, 3.5-5.5 months). Intent to treat median survival time was 8.9 months. Forty-eight percent of the patients experienced catheter-related events. CONCLUSIONS: LY900003 can be administered safely in combination with cisplatin and gemcitabine and is associated with antitumor activity in patients with advanced NSCLC. Better characterization of subsets of patients most likely to benefit from this combination therapy is needed.

Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy.

PURPOSE: This phase II study evaluated the safety and efficacy of single-agent amrubicin versus topotecan in patients with small-cell lung cancer (SCLC) sensitive to first-line platinum-based chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned 2:1 to amrubicin (40 mg/m(2)/d in a 5-minute intravenous [IV] infusion, days 1 through 3, every 21 days) or topotecan (1.5 mg/m(2)/d in a 30-minute IV infusion, days 1 through 5, every 21 days). The primary efficacy end point was overall response rate (ORR) for amrubicin. Secondary end points included time to progression, median progression-free survival (PFS), and median overall survival (OS). RESULTS: Of 76 patients enrolled, 50 patients were randomly assigned to amrubicin, and 26 patients were randomly assigned to topotecan. Amrubicin treatment resulted in a significantly higher ORR than topotecan (44% v 15%; P = .021). Median PFS and median OS were 4.5 months and 9.2 months with amrubicin and 3.3 months and 7.6 months with topotecan, respectively. Tolerability was similar with both agents. However, grade 3 or worse neutropenia and thrombocytopenia seemed to be more frequent in the topotecan group as compared with the amrubicin group (78% and 61% v 61% and 39%, respectively). CONCLUSION: Amrubicin shows promising activity, with an ORR of 44% compared with an ORR of 15% for topotecan as second-line treatment in patients with SCLC sensitive to first-line platinum-based chemotherapy. In addition, the safety profiles were comparable; however, a trend was noted for more frequent grade 3 or worse neutropenia and thrombocytopenia in the topotecan group as compared with the amrubicin group. Additional studies are ongoing.

Phase II study of amrubicin as second-line therapy in patients with platinum-refractory small-cell lung cancer.

PURPOSE: Amrubicin is a synthetic anthracycline with potent topoisomerase II inhibition. This phase II study was conducted to confirm safety and activity of amrubicin in the treatment of refractory small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with refractory SCLC (either with progressive disease as best response or progression within 90 days of first-line therapy) received amrubicin (40 mg/m(2)/d for 3 every 21 days). The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), and change in left ventricular ejection fraction (LVEF). RESULTS: Seventy-five patients with a median progression-free interval after first-line therapy of 38 days were enrolled; 69 patients received a median of four amrubicin cycles (range, one to 12 cycles). The ORR was 21.3% (95% CI, 12.7% to 32.3%), with one complete response (1.3%) and 15 partial responses (20%). Median PFS and OS were 3.2 months (95% CI, 2.4 to 4.0 months) and 6.0 months (95% CI, 4.8 to 7.1 months), respectively. The ORR in 43 patients who never responded to first-line therapy was 16.3% (95% CI, 6.8% to 30.7%). Most commonly reported grade 3 or 4 adverse events included neutropenia (67%), thrombocytopenia (41%), and anemia (30%), with febrile neutropenia in 12%. There was no decrease in mean LVEF with cumulative amrubicin doses exceeding 750 mg/m(2). CONCLUSION: Single-agent amrubicin showed promising activity with a 21.3% ORR and an acceptable safety profile when used as second-line therapy patients with platinum-refractory SCLC. Amrubicin did not induce early cardiotoxicity, but its long-term effects are unknown.

Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study.

PURPOSE: Bendamustine hydrochloride is an alkylating agent with novel mechanisms of action. This phase II multicenter study evaluated the efficacy and toxicity of bendamustine in patients with B-cell non-Hodgkin's lymphoma (NHL) refractory to rituximab. PATIENTS AND METHODS: Patients received bendamustine 120 mg/m(2) intravenously on days 1 and 2 of each 21-day cycle. Outcomes included response, duration of response, progression-free survival, and safety. RESULTS: Seventy-six patients, ages 38 to 84 years, with predominantly stage III/IV indolent (80%) or transformed (20%) disease were treated; 74 were assessable for response. Twenty-four (32%) were refractory to chemotherapy. Patients received a median of two prior unique regimens. An overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) was observed. The median duration of response was 6.7 months (95% CI, 5.1 to 9.9 months), 9.0 months (95% CI, 5.8 to 16.7) for patients with indolent disease, and 2.3 months (95% CI, 1.7 to 5.1) for those with transformed disease. Thirty-six percent of these responses exceeded 1 year. The most frequent nonhematologic adverse events included nausea and vomiting, fatigue, constipation, anorexia, fever, cough, and diarrhea. Grade 3 or 4 reversible hematologic toxicities included neutropenia (54%), thrombocytopenia (25%), and anemia (12%). CONCLUSION: Single-agent bendamustine produced durable objective responses with acceptable toxicity in heavily pretreated patients with rituximab-refractory, indolent NHL. These findings are promising and will serve as a benchmark for future clinical trials in this novel patient population.