PEMBROLIZUMAB + AXITINIB ENHANCES OUTCOMES IN INTERMEDIATE/POOR RISK AND SARCOMATOID MRCC
Abstract 4500: Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study
The intermediate/poor risk and sarcomatoid subgroups of the phase III KEYNOTE-426 study in metastatic renal cell carcinoma were discussed by Dr. Brian I. Rini (Cleveland Clinic, Cleveland, OH). In the previous report of all IMDC risk groups, pembrolizumab + axitinib (P+A) benefit was observed in the overall population compared to sunitinib (S) treatment. In the present study, OS and PFS were presented for the two aforementioned subgroups, with ORR as the secondary endpoint.
68.8% of the total KEYNOTE-426 study population was poor/intermediate risk, and these patients experienced enhanced OS and PFS when treated with P+A compared to S (OS HR:0.52; PFS HR: 0.67). Improved ORR was also measured in the PD-1 blockade arm, at 55.8%, compared to 29.5% with S. Sarcomatoid features were observed in 18.2% of the total patient population, and these patients also enjoyed enhanced OS, PFS, and ORR with P+A compared to S (OS HR: 0.58, PFS HR: 0.54, ORR: 58.8% vs 31.5%). This study provides further very promising support to the use of pembrolizumab + axitinib in these subpopulations of mRCC.
PRE-SURGERY IMMUNE CHECKPOINT BLOCKADE IS SAFE IN METASTATIC RCC
Abstract 4501: A pilot randomized study evaluating nivolumab (nivo) or nivo + bevacizumab (bev) or nivo + ipilimumab (ipi) in patients with metastatic renal cell carcinoma (MRCC) eligible for cytoreductive nephrectomy, metastasectomy or post-treatment biopsy (Bx)
Patients with metastatic renal cell carcinoma were treated with combination checkpoint inhibition prior to surgery or biopsy in a study presented by Dr. Jianjun Gao (MD Anderson Cancer Center, Houston, TX). Three pre-surgical regimens were employed, randomized 2:3:2 - nivolumab (N, 3 mg/kg Q2W x3), nivolumab + bevacizumab (N+B, B 10 mg/kg Q2W x3), and nivolumab + ipilimumab (N+I, I 1 mg/kg Q3W x2). After completion of the respective regimens and surgical intervention, patients could undergo N maintenance therapy for up to two years. Of note, this trial was not designed to compare between treatment arms; rather, safety was the primary endpoint, with secondary endpoints including biomarkers and best overall response.
In the total population, best overall response (BOR = PR + CR, including surgery effect) was 59% for N, 44% for N+B, and 43% for N+I. OS in the total population at two years was 72% for N, 60% for N+B, and 56% for N+I. For the subgroup of patients that underwent cytoreductive surgery, BOR was 86% for N, 82% for N+B, and 69% for N+I, and the OS at two years was 84% in the total population. Overall, grade 3 or greater treatment-related toxicities occurred in 28% of N, 38% of N+B, and 43% of N+I patients. Biomarker analyses indicated that tumor-infiltrating CD8 T cells correlated with response to N or N+B, and IFN gene expression correlated with response in all groups. Predicted neoantigen presence and TMB were not correlated with outcomes in this study.
MAINTENANCE PEMBROLIZUMAB ENHANCES PFS IN METASTATIC UROTHELIAL CANCER PATIENTS COMPARED TO MAINTENANCE CHEMOTHERAPY
Abstract 4504: Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182
A "switch maintenance" approach was proposed by Dr. Matt D. Galsky (Mount Sinai, New York, NY) in a study of metastatic urothelial cancer. Patients with at least stable disease after 8 or less cycles of Pt-based chemotherapy were randomized to pembrolizumab 200 mg Q3W versus placebo for up to 24 months, and patients progressing on placebo could cross over to pembro. The primary endpoint of this study was PFS.
Excluding patients who had CRs from initial chemotherapy, pembro provided enhanced objective response rates over placebo (22% vs 12%), and patients randomized to pembro had significantly longer PFS compared to placebo (18-month restricted mean: 8.1 vs 5.5 mo, maximum efficiency robust test p=0.036). After a median of 14.7 months, 26/52 patients randomized to placebo had crossed over to the pembro arm. Treatment-emergent AEs of grade 3-4 occurred in 53% of pembro patients and 35% of placebo. The authors suggest that switch-maintenance pembrolizumab may thus help "deepen" responses to chemotherapy.
DURVALUMAB IMPROVES OUTCOMES FOR DMMR ENDOMETRIAL CANCER
Abstract 5501: Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: The phase II PHAEDRA trial (ANZGOG1601)
Dr. Yoland Catherine Antill (Cabrini Health, Malvern, Australia) presented a phase II study of durvalumab treatment in advanced endometrial cancer. Patients with proficient MMR (pMMR) had progressed after 1-3 lines of chemotherapy, while patients with deficient MMR (dMMR) had 0-3 previous lines of chemotherapy, prior to all receiving 1500 mg durvalumab Q4W. The primary endpoint was objective tumor response (OTR=CR+PR), and presented secondary measures included disease control at 16 weeks (DC16w) and adverse events.
In AEC patients with dMMR, an encouraging OTR of 43% (15/35) was observed, comprising 5 CR and 10 PR. Adding in the 8 patients with SD gave a DC16w of 60%. The DCR at data cut-off for the presentation had increased to 66%. When used as a first-line treatment, the OTR rate was 52% in this population, and 31% in the 2nd-line setting. When considering patients with pMMR, the OTR rate was only 3% (1 PR), while 9 other patients had SD, giving a DC16w of 20%. Overall, irAEs occurred in 14 patients. This study supports the use of durvalumab in dMMR AEC, but limited efficacy was seen when MMR machinery was proficient.
HIGH RESPONSE RATES IN MSI ENDOMETRIAL CANCER TREATED WITH AVELUMAB
Abstract 5502: Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC)
Avelumab was studied in recurrent/persistent endometrial cancer by Dr. Panagiotis A. Konstantinopoulos (Dana-Farber Cancer Institute, Boston, MA) and co-workers. The presented results explored PD-L1 blockade (avelumab 10 mg/kg Q2W) in two EC populations: those with MSI/POLE loss of expression or mutation, and those with normal MMR protein expression (MSS). Co-primary endpoints of this study were confirmed objective response (OR) and PFS at 6 months.
In the MSS cohort, only one patient (out of 16) in the 1st stage of the trial demonstrated an OR and PFS6 response, causing this cohort to close after the first stage. The study planned to enroll POLE-mutated patients, but in actuality none were included. However, encouraging efficacy was seen in the MSI population: four patients out of 15 evaluable patients exhibited an OR (with 1 CR and 3 PRs). Six patients were progression-free at 6 months and the median OS had not yet been reached. The most common TRAEs were fatigue and nausea. The assay that was used to determine MSI status was found to be of importance: the three compared tools (IHC, PCR, ONCOPANEL) led to different allocation of patients between the MSS/MSI arms in a few cases, highlighting the need for validation of these instruments. PD-L1 positivity, TMB, and TILs were not found to correlate with outcomes in this study, but a number of genetic signatures were identified.