Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206

Background Despite remarkable results with salvage standard-dose or high-dose chemotherapy ∼15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT. Patients and methods Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized. Results Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1–32, 760) and hCG 4 (range 0.6–37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1–8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining. Conclusion This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT

Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers

Patients and methods: Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. Results: From April 2014-October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). Conclusion: Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy

Dose optimization of novel BRAF inhibitor FORE8394 based on PK and efficacy results

3106 Background: FORE8394 is a selective inhibitor of class 1 (V600) and 2 (activating non-V600) BRAF alterations that avoids paradoxical MAPK pathway activation. Consistent with the paradigm shift to optimal dosing vs identifying the maximal tolerated dose, integrated pharmacokinetic (PK), genomics, safety, and efficacy data, and exposure-response modeling were used to identify the recommended dose (RD). Methods: In a single arm phase 1/2a study, patients (pts) age ≥3 years with advanced solid or CNS tumors with BRAF alterations received FORE8394 900-3600 mg/day with or without the PK enhancer cobicistat (cobi) until progression. Efficacy pts had class 1 or 2 BRAF alterations & ≥1 post-baseline assessment (mITT); the BRAF V600 MAPKi naïve, non CRC subset provided a homogenous subset to also inform dose selection. PK was evaluated after single and repeated dosing. Results: To date, 110 pts (age range 4-86 years) received ≥1 dose of FORE8394; 58% had ≥2 prior lines of therapy, 25% had prior MAPKi. PK was independent of age or weight. Cobi increased FORE8394 exposure 2-3-fold. Exposure increased with dose, with less than proportional increase at doses >900 mg BID. Higher Cmax and trough levels were achieved with QD vs BID/TID. Objective (confirmed) responses were observed at all doses; however, objective response rate (ORR) was greatest (50%) at 900mg QD + cobi, with no further increases in ORR at higher doses. Dose-limiting toxicities were only observed at doses ≥1500 mg/day + cobi: 1500-1800 mg/day (4) and 2700-3600 mg/day (1). Similarly, treatment-emergent adverse events (TEAEs) ≥Grade 3 (G3) increased at the higher doses. Only 1 pt discontinued FORE8394 due to treatment-related AE (G3 bilirubin; 3600 mg/day). Conclusions: Based on the entirety of safety, PK, and efficacy data, the optimal RD of FORE8394 in Phase 2 is 900 mg QD + cobi in pts ≥10 years old. This achieved targeted efficacious exposures with robust antitumor activity and favorable safety. This dose optimization is consistent with current guidelines, avoids higher exposure that may lead to higher toxicity and compromise dose intensity. QD dosing also allows for a convenient dosing regimen. A Phase 2 study at the RD is ongoing in pts with recurrent V600E BRAF-mutated primary CNS tumors and advanced solid or CNS tumors with BRAF fusions. Clinical trial information: NCT02428712 . [Table: see text