Initial results from a phase II study of nivolumab plus ipilimumab for the treatment of metastatic castration-resistant prostate cancer (CheckMate 650)
Padmanee Sharma, MD, PhD (MD Anderson Cancer center, Houston, TX) presented phase II data from CheckMate 650 (NCT02985957), investigating safety and efficacy of the combination therapy nivolumab plus ipilimumab in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), a population that does not traditionally respond to immune checkpoint inhibition. Treatment included nivolumab at a dose of 1 mg/kg plus ipilimumab at a dose of 3 mg/kg every 3 weeks for 4 doses, then nivolumab alone at a dose of 480 mg every 4 weeks. This study assessed two cohorts of patients: asymptomatic or minimally symptomatic patients who progressed after hormone therapy but had not yet received chemotherapy for mCRPC (cohort 1) and patients who progressed after taxane-based chemotherapy (cohort 2). Of the treated patients, 78 had a minimum follow-up of 6 months. For patients with baseline measurable disease, overall response rate (ORR) was 26% (6/23, 95% CI: 10-48) and 10% (3/30, 95% CI: 2-27) in cohorts 1 and 2. In both cohorts, ORR was higher in patients with PD-L1 ≥1% vs. PD-L1 <1% (cohort 1: [2/4] 50% vs. [4/23] 17%; cohort 2: [2/8] 25% vs. [0/20] 0%). ORR was similarly higher for both cohorts in patients positive for DNA damage repair (DDR) and homologous recombination deficiency (HRD), and those who tested above the median tumor mutational burden (TMB). Of all PSA responding patients, 4 had PSA <0.2 ng/mL. Grade 3–4 TRAEs occurred in 39% and 51% of patients (cohorts 1 and 2, respectively) and one grade 5 event occurred in each cohort, perhaps due to the high dose if ipilimumab. Overall, the combination therapy nivolumab plus ipilimumab demonstrated activity in a population of patients who were not expected to respond to ICI therapy, with an enriched response in biomarker-expressing subpopulations.
Keynote-365 cohort a: Pembrolizumab plus olaparib in docetaxel-pretreated patients with metastatic castrate-resistant prostate cancer
Evan Y. Yu, MD (Seattle Cancer Care Alliance, Seattle, WA) reported preliminary results from cohort a of KEYNOTE-365 (NCT02861573), a phase 1b/2 study testing the combination of checkpoint blockade therapy with pembrolizumab plus PARP inhibition by olaparib in mCRPC. Patients with mCRPC were eligible for this clinical trial if they progressed within 6 months prior to screening determined by either PSA progression or radiologic progression in bone or soft tissue. Patients in this study had received prior treatment with docetaxel for mCRPC, may have received 1 other chemotherapy, and had ≤2 2nd-generation hormone therapies. At the median follow-up of 11 months, of the 41 patients who had initiated treatment, 27% were PD-L1+, 42% had visceral disease and 68% were RECIST-measurable. Efficacy results included ORR: 2/28 (7%, 2 PRs), measurable disease: 9/28 (32%), nonmeasurable disease: 3/13 (23% delete space), median time to confirmed PSA progression: 16 weeks (CI: 14, 21), median progression free survival (PFS) per PCWG-modified RECIST: 5 months (CI: 4, 8) and median overall survival (OS): 14 months (CI: (8, NR). TRAEs occurred in 39 (95%) patients, most frequently including, anemia (≥30%), fatigue (37%), and nausea (34%). Grade 3-5 TRAEs were observed in 21 (51%) patients. 2 deaths occurred, with 1 being treatment-related. In summary, the combination therapy pembrolizumab plus olaparib has demonstrated initial activity in previously treated patients with mCRPC with safety profile consistent with previous reports.
Keynote 057: Phase II trial of Pembrolizumab for patients with high-risk nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG)
Arjun Balar, MD (NYU Langone – Perlmutter Cancer Center, New York, NY) discussed phase II trial data from the single arm Keynote-057 (NCT02625961) study which examined the use of pembrolizumab in patients with high-risk (HR), BCG-unresponsive NMIBC. Results for patients with carcinoma in situ with or without papillary tumor and who were unable/unwilling to undergo radical cystectomy were reported. Patients received pembrolizumab at a dose of 200mg every 3 weeks for 24 months or until recurrence, progression or toxicity. 103 patients (71.8% without papillary tumor and a median of 12 prior BCG instillations) were enrolled in the reported cohort. The 3-month complete response (CR) rate was observed in 40/103 patients (38.8%; 95% CI 29.4%-48.9%). Among these patients, 72.5% maintained CR at last follow-up (median 14.0 months; range 4.0-26.3) and median CR duration has not been reached (range 0+ to 14.1+ months). 80.2% of patients had a CR duration of ≥6 months. 10 of the 40 complete responders (25.0% delete space) experienced recurrent NMIBC after CR, although none had progressed to muscle invasive or metastatic disease at the time of analysis. TRAEs occurred in 65 (63.1%) patients, most frequently involving pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). Grade 3/4 TRAEs occurred in 13 (12.6%) patients, including 1 death (colitis). irAEs occurred in 18.4% of patients.
Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab + ipilimumab or sunitinib in patients with advanced renal cell carcinoma
Nizar M. Tannir, MD, FACP (MD Anderson Cancer Center, Houston, TX) detailed 30-month follow-up results of the phase III CheckMate 214 clinical trial (NCT02231749), assessing first-line combination therapy nivolumab plus ipilimumab vs. sunitinib in patients with advanced renal cell carcinoma (aRCC). This report follows the 17.5 month follow-up of the same study which reported superior OS in the intent to treat (ITT) population as well as in the primary population of patients with intermediate/poor-risk (I/P). At 30 month min follow-up, OS remained significantly improved in ITT and I/P patients treated with combination immunotherapy. The HR for OS in favorable risk patients was 1.22 [95% CI 0.73–2.04]). Increased PFS benefit with the combination immunotherapy emerged in both the ITT and I/P populations. At the time of reporting, 15% and 9% of nivolumab plus ipilimumab and sunitinib ITT patients, respectively, remained on therapy, and 48% vs 61% have since received 2nd-line systemic therapy (39% of patients in the sunitinib arm received subsequent ICI therapy). Among patients with CR, 50% vs 10% remain on treatment with the combination immunotherapy vs sunitinib. No new drug-related deaths occurred. In conclusion, at 30 months follow-up, OS, PFS, and ORR continue to show improved benefit compared to sunitinib in ITT and I/P patients, while no statistical difference was observed between the arms for OS, PFS, or ORR in the favorable-risk subgroup. Overall, in patients treated with the combination checkpoint therapy, notable CR rates were observed as well as deeper, more durable responses.
Results of a phase II study of atezolizumab and bevacizumab in non-clear cell renal cell carcinoma and clear cell renal cell carcinoma with sarcomatoid differentiation
Rana R. McKay, MD (UC San Diego Health, La Jolla, CA) presented phase II data regarding the combined use of atezolizumab plus bevacizumab in patients with non-clear cell renal cell carcinoma (nccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (sccRCC), patient populations underrepresented in kidney cancer clinical trials. Of the 65 enrolled patients, 52 were eligible for assessment in this analysis. 36 patients had nccRCC (papillary n=14, chromophobe n=8, unclassified RCC n=3, collecting duct n=3, translocation n=3, other n=5), and 16 patients had sccRCC. 17 patients received prior systemic therapy. In the overall cohort, ORR was observed in 16/52 patients (31%), including 7/16 (44%) in sccRCC, 9/36 (25%) in nccRCC, 8/35 (23%) treatment naïve and 8/17 (47%) who received prior systemic therapy. Stable disease was witnessed in 23/52 (44%) patients including 5/16 (31%) in sccRCC, 18/36 (50%) in nccRCC, 18/35 (51%) treatment naïve and 5/17 (29%) who received prior systemic therapy. 10 patients (19%) developed grade 3 TRAEs (about 50% immune-related. In summary, the IO/TKI combination of atezolizumab plus bevacizumab was deemed safe and demonstrated anti-tumor efficacy in both nccRCC and sccRCC patients.
Pembrolizumab plus axitinib versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma: phase III KEYNOTE-426 study
Thomas Powles, MD, PhD, FCRP (Barts Cancer Institute, London, United Kingdom) reported data from Keynote-426 (NCT02853331), a randomized, phase III study investigating the use of pembrolizumab plus axitinib vs. sunitinib in first-line treatment of mRCC (n=861 patients). At a median follow-up of 12.8-months, 59.0% of patients in the pembroliziumab plus axitinib arm and 43.1% in the sunitinib arm continued to receive treatment. Pembrolizumab plus axitinib significantly improved OS (HR 0.53 [95% CI 0.38-0.74]; P< 0.0001; 12-mo rate 89.9% vs 78.3%), PFS (HR 0.69 [95% CI 0.57-0.84]; P = 0.0001; median 15.1 vs 11.1 mo), and ORR (59.3% vs 35.7%; P< 0.0001). Duration of response was also enhanced with pembrolizumab plus axitinib (median not reached vs 15.2 mo). Importantly, benefit from pembrolizumab plus axitinib was reported across all IMDC risk and regardless of PD-L1 expression. TRAEs grade 3-5 were experienced in 62.9% of patients in the pembrolizumab plus axitinib arm vs 58.1% in the sunitinib arm and led to regimen discontinuation in 6.3% vs 10.1%, respectively. These data demonstrate a clinically significant response and impressive survival benefit for mRCC patients treated with pembrolizumab plus axitinib establishing this regimen as a standard of care.
Subgroup analysis from JAVELIN Renal 101: Outcomes for avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma
Toni K. Choueiri, MD (Dana-Farber Cancer Institute, Boston MA) detailed outcomes from subgroups of the phase III JAVELIN Renal 101 clinical trial (NCT02684006), assessing avelumab plus axitinib vs. sunitinib in patients with advanced renal cell carcinoma (aRCC). Of the 886 total patients enrolled, 560 (63%) had PD-L1+ tumors. At data cut-off (Jun 2018), median follow-up was 12.0 vs 11.5 months for avelumab plus axitinib vs sunitinib groups. PFS and ORR were categorized by MSKCC and IMDC risk groups (favorable; intermediate; poor) and PD-L1 subgroups. Avelumab plus axitinib demonstrated improvement in PFS and ORR across all prognostic risk groups and PD-L1 subgroups. Overall survival data is currently pending.
First-line pembrolizumab monotherapy for advanced non-clear cell renal cell carcinoma: Results from KEYNOTE-427 cohort B
David F. McDermott, MD (Beth Israel Deaconess Medical Center, Boston, MA) discussed the results of Keynote-427 (NCT02853344) cohort B, a single-arm, phase II study of pembrolizumab monotherapy in patients with advanced non-clear cell renal cell carcinoma (anccRCC). 165 treatment naïve patients with anccRCC were enrolled to receive pembrolizumab at 200 mg every 3 weeks for 35 cycles (about 2 years) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Patients were followed after PD for OS. 68% of patients were classified as intermediate/poor IMDC risk, and 62% were PD-L1+. Histologies included: papillary 72% (n=118), chromophobe 13% (n=21), unclassified 16% (n=26). At a median follow-up of 11.1 months (range, 0.9-21.3), 56% of patients discontinued pembrolizumab due to progression. ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CRs, 33 [20%] PRs). In patients with favorable risk, ORR (95% CI) was 28.3% (16.8-42.3) compared to 23.2% (15.8-32.1) in patients with intermediate/poor IMDC risk. Furthermore, OR was 33.3% (24.3-43.4) and 10.3% (3.9-21.2) for patients whose tumors had scores of CPS≥1 and CPS<1, respectively. Regarding specific histologies, ORR was 25.4% (17.9-34.3) in papillary, 9.5% (1.2-30.4) in chromophobe, and 34.6% (17.2-55.7) in unclassified nccRCC. Grade 3-5 TRAEs occurred in 11% of patients, with 6% of patients having discontinued therapy due to TRAEs, 6 deaths due to AEs (including 2 TRAEs: pneumonia and cardiac arrest).