Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: This open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual-action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck. METHODS: On day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m2 and 5-fluorouracil at a dose of 1000 mg/m2 /day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6 mg/mL/min) and paclitaxel (at a dose of 200 mg/m2 ) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred. RESULTS: Nine patients in arm A and 15 patients in arm B received a median of 6 cycles of chemotherapy, and a median of 11 cycles (arm A) and 9 cycles (arm B) of duligotuzumab. Dose-limiting toxicities occurred in 3 patients in arm A and 1 patient in arm B. Grade ≥ 3 treatment-related adverse events (graded according to graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) in ≥ 3 patients were neutropenia (5 patients), hypokalemia (4 patients), dehydration (3 patients), anemia (3 patients), and diarrhea (3 patients) in arm A, and neutropenia (8 patients), anemia (5 patients), febrile neutropenia (4 patients), leukopenia (3 patients), thrombocytopenia (3 patients), and hypomagnesemia (3 patients) in arm B. The chemotherapy dose was reduced in 19 of 24 patients. Sixteen patients (67%) demonstrated objective responses regardless of human papillomavirus status or neuregulin 1 (NRG1) mRNA expression (arm A: 2 confirmed complete responses and 4 confirmed partial responses; arm B: 2 confirmed complete responses and 8 confirmed partial responses). CONCLUSIONS: Duligotuzumab in combination with cisplatin/5-fluorouracil or carboplatin/paclitaxel demonstrated encouraging activity in patients with recurrent/metastatic squamous cell cancer of the head and neck; an association with increased frequency and severity of select adverse events relative to historical data was suggestive of the potentiation of chemotherapy-related adverse events. Cancer 2016;122:3803-3811. © 2016 American Cancer Society.

A phase Ib/II trial of capmatinib plus spartalizumab vs. spartalizumab alone in patients with pretreated hepatocellular carcinoma.

Background & aims: This phase Ib/II trial evaluated the safety and efficacy of capmatinib in combination with spartalizumab or spartalizumab alone in patients with advanced hepatocellular carcinoma (HCC). Methods: Eligible patients who had progressed or were intolerant to sorafenib received escalating doses of capmatinib 200 mg, 300 mg, and 400 mg twice a day (bid) plus spartalizumab 300 mg every 3 weeks (q3w) in the phase Ib study. Once the recommended phase II dose (RP2D) was determined, the phase II study commenced with randomised 1:1 treatment with either capmatinib + spartalizumab (n = 32) or spartalizumab alone (n = 30). Primary endpoints were safety and tolerability (phase Ib) and investigator-assessed overall response rate per RECIST v1.1 for combination vs. single-agent arms using a Bayesian logistic regression model (phase II). Results: In phase Ib, the RP2D for capmatinib in combination with spartalizumab was determined to be 400 mg bid. Dose-limiting toxicity consisting of grade 3 diarrhoea was reported in one patient at the capmatinib 400 mg bid + spartalizumab 300 mg q3w dose level. The primary endpoint in the phase II study was not met. The observed overall response rate in the capmatinib + spartalizumab arm was 9.4% vs. 10% in the spartalizumab arm. The most common any-grade treatment-related adverse events (TRAEs, ≥20%) were nausea (37.5%), asthenia and vomiting (28.1% each), diarrhoea, pyrexia, and decreased appetite (25.0% each) in the combination arm; TRAEs ≥10% were pruritus (23.3%), and rash (10.0%) in the spartalizumab-alone arm. Conclusion: Capmatinib at 400 mg bid plus spartalizumab 300 mg q3w was established as the RP2D, with manageable toxicities and no significant safety signals, but the combination did not show superior clinical activity compared with spartalizumab single-agent treatment in patients with advanced HCC who had previously been treated with sorafenib. Impact and implications: Simultaneous targeting of MET and programmed cell death protein 1 may provide synergistic clinical benefit in patients with advanced HCC. This is the first trial to report a combination of capmatinib (MET inhibitor) and spartalizumab (programmed cell death protein 1 inhibitor) as second-line treatment after sorafenib for advanced HCC. The combination did not show superior clinical activity compared with spartalizumab single-agent treatment in patients with advanced HCC who had previously been treated with sorafenib. The results indicate that there is a clear need to identify a reliable predictive marker of response for HCC and to identify patients with HCC that would benefit from the combination of checkpoint inhibitor +/- targeted therapy. Clinical trial number: NCT02795429.

Capmatinib plus nivolumab in pretreated patients with EGFR wild-type advanced non-small cell lung cancer.

INTRODUCTION: Dysregulated MET is an established oncogenic driver in non-small cell lung cancer (NSCLC). MET signaling may also suppress anticancer immune responses. Concomitant MET inhibition with capmatinib (a MET inhibitor) synergistically enhanced the efficacy of immunotherapies in murine cancer models, regardless of tumor dependency to MET signaling. Here, we report results of a multicenter, open-label, phase 2 study of capmatinib plus nivolumab (a PD-1 inhibitor) in patients with EGFR wild-type advanced NSCLC, previously treated with platinum-based chemotherapy. METHODS: Patients were allocated into high-MET or low-MET groups according to MET expression determined by immunohistochemistry, MET gene copy number as assessed by fluorescence in-situ hybridization, and presence of MET exon 14 skipping mutation, then received capmatinib 400 mg, oral, twice daily in combination with nivolumab 3 mg/kg intravenously every 2 weeks. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate per RECIST v1.1. RESULTS: The primary endpoint was met in both the high-MET (N = 16) and low-MET (N = 30) groups. In the high-MET and low-MET groups, respectively, the estimated mean 6-month PFS rate (95 % credible interval) by Bayesian analysis was 68.9 % (48.5-85.7) and 50.9 % (35.6-66.4). The Kaplan-Meier median PFS (95 % CI) was 6.2 months (3.5-19.2) and 4.2 months (1.8-7.4). The overall response rate (95 % CI) was 25.0 % (7.3-52.4) and 16.7 % (5.6-34.7). Most frequent treatment-related adverse events (≥30 % any grade, N = 46) were nausea (52.2 %), peripheral edema (34.8 %), and increased blood creatinine (30.4 %). CONCLUSIONS: Capmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323126.

Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer.

Our goal was to optimize the radiosensitizing potential of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, when given concomitantly with preoperative radiotherapy in KRAS wild-type locally advanced rectal cancer (LARC). Based on pre-clinical studies conducted by our group, we designed a phase II trial in which panitumumab (6 mg/kg/q2 weeks) was combined with preoperative radiotherapy (45 Gy in 25 fractions) to treat cT3-4/N + KRAS wild-type LARC. The primary endpoint was complete pathologic response (pCR) (H0 = 5%, H1 = 17%, α = 0.05, ß = 0.2). From 19 enrolled patients, 17 (89%) were evaluable for pathology assessment. Although no pCR was observed, seven patients (41%) had grade 3 Dworak pathological tumor regression. The regimen was safe and was associated with 95% of sphincter-preservation rate. No NRAS, BRAF, or PI3KCA mutation was found in this study, but one patient (5%) showed loss of PTEN expression. The quantification of plasma EGFR ligands during treatment showed significant upregulation of plasma TGF-α and EGF following panitumumab administration (p < 0.05). At surgery, patients with important pathological regression (grade 3 Dworak) had higher plasma TGF-α (p = 0.03) but lower plasma EGF (p = 0.003) compared to those with grade 0-2 Dworak. Our study suggests that concomitant panitumumab and preoperative radiotherapy in KRAS wild-type LARC is feasible and results in some tumor regression. However, pCR rate remained modest. Given that the primary endpoint of our study was not reached, we remain unable to recommend the use of panitumumab as a radiosensitizer in KRAS wild-type LARC outside a research setting.

Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer.

PURPOSE: We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Six patients were included per dose level. Following docetaxel infusion on day 1 (75 mg/m(2)/q3 weeks), sorafenib was administered at 200 mg BID on days 2-19 (dose level 1), at 200 mg BID on days 1-21 (dose level 2), at 400 mg BID on days 2-19 (dose level 3), at 400 mg BID on days 1-21 (dose level 4). Maximal tolerated dose (MTD) was exceeded if ≥2 patients experienced dose-limiting toxicities (DLT) during cycle 1. The recommended phase 2 dose for sorafenib was defined as one dose level below MTD. If MTD was not reached, the highest feasible dose would be selected to treat an expanded cohort to confirm safety. RESULTS: Two DLTs were observed during sorafenib dose-escalation consisting of grade 4 febrile neutropenia (dose level 2) and grade 3 hand-foot syndrome (HFS) (dose level 3). Our pharmacokinetic results showed an increased exposure to docetaxel across all dose levels during sorafenib comedication. The main grade ≥3 toxicities were neutropenia (35 %), HFS (27 %), and febrile neutropenia (19 %). The prostate-specific antigen (PSA) response rate was 74 %. Median overall survival was 25.2 months. CONCLUSION: Three-weekly docetaxel and prednisone could be combined with sorafenib at 400 mg BID on days 1-21 without reaching MTD. However, we observed a pharmacokinetic interaction between sorafenib and docetaxel, associated with significant toxicities, raising concerns about the safety of this combination in mCRPC.