Konstantin Penkov

BACKGROUND: In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib. METHODS: We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety. RESULTS: A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups. CONCLUSIONS: Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).

101 Background: The phase 3 JAVELIN Renal 101 trial in previously untreated patients (pts) with aRCC demonstrated a progression-free survival (PFS) benefit and higher objective response rate with A+Ax vs S (Motzer, ESMO 2018; LBA6_PR). Here, we report outcomes from biomarker analyses of baseline tumor samples. Methods: We correlated efficacy with the results of molecular analyses of tissue samples from all 886 pts enrolled in JAVELIN Renal 101. Nephrectomy or tumor samples were characterized by immunohistochemistry (CD8 and PD-L1), whole-exome sequencing (WES), and RNAseq. WES and RNAseq were used to examine somatic mutations and analyze relevant gene expression signatures (GES) in relation to clinical outcomes. GES analyses included published and de novo signatures: effector T cell (T eff ), angiogenesis (angio),T cell-inflamed (T inf ), and a novel immune-related signature incorporating pathway indicators for T- and NK-cell activation and IFNγ signaling, among others. Results: PD-L1 expression (≥1% immune cells) was associated with the longest PFS in the A+Ax arm and the shortest in the S arm (HR, 0.63; 95% CI, 0.49, 0.81). Significant treatment arm–specific differences in PFS were observed relative to wildtype when mutations in genes such as CD1631L, PTEN, or DNMT1 were present. Tumor mutational burden did not distinguish pts with respect to PFS. High-angio GES was associated with significantly improved PFS in the S arm but did not differentiate PFS in the A+Ax arm. In the low-angio subset, A+Ax improved PFS vs S. Pts with high T eff and T inf in the A+Ax arm had longer PFS vs the S arm. In the A+Ax arm, PFS was enhanced in patients with immune GES–positive tumors vs those in the negative group (HR, 0.63; 95% CI, 0.46, 0.86; 2-sided p = 0.004), as well as in an independent dataset (JAVELIN Renal 100; Choueiri, Lancet Oncol, 2018) (HR, 0.46; 95% CI, 0.20, 1.05; 2-sided p = 0.064). Updated efficacy, including overall survival, will be presented. Conclusions: These findings define molecular features that differentiate therapy-specific outcomes in first-line aRCC and may inform personalized therapy strategies for pts with aRCC. Funding: Pfizer and Merck KGaA. Clinical trial information: NCT02684006.

PURPOSE: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4-6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. RESULTS: = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36-0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09-1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. CONCLUSIONS: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.