Unpacking the Virtual ASCO 2020 Sessions: What’s New in the RCC Toolbox?

Despite the unprecedented virtual nature of its program, this year’s American Society of Clinical Oncology (ASCO) fulfilled its promise of offering a “diverse program, a multidisciplinary perspective, and a wealth of new research, and limitless opportunities for discovery” as thousands of oncologists around the world gather virtually to learn about the latest research in cancer. In ASCO20 meeting alone, the impactful results from several major trials have once again changed rapidly evolving landscape of front-line treatment for patients with advanced RCC.

A review of highlights from the sessions suggests how latest breakthrough results could:

  • Open up an avenue of a new class therapy: HIF-2α inhibitor MK-6428 owing to its promising efficacy and tolerability in patients with advanced RCC.
  • Further clarify multiple choices in frontline therapy, including the immune checkpoint inhibitor (ICI) therapy alone or combination with tyrosine kinase inhibitor (TKI).
  • Addressing whether it is appropriate to sequence PD-1 inhibitor vs using them in combination
  • Help us assess the association of gene expression signatures and DNA alterations with response or resistance to immunotherapy.
  • Provide important clues about angiogenic and myeloid expression markers to stratify patients based on transcriptomic profile and its prognostic significance.

The abstracts included in this report have been selected by Robert A. Figlin, MD, Editor-in- Chief of the Kidney Cancer Journal and appear in an abbreviated format due to space constraints. The chosen abstracts provided here highlight some of the most important trends in ongoing trials and reflect the foremost research and strategies from latest clinical trials that impact the current standard of care in renal cancer.

Full abstracts can be viewed on our KCJ website, please check out: https://kidney-cancer- journal.com/asco.php.

Abstract 5001: Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): Updated analysis of KEYNOTE-426.

Elizabeth R. Plimack, Brian I. Rini, Viktor Stus et al.

Results: 861 pts were randomly assigned (pembro + axi, n = 432; sunitinib, n = 429). Median (range) duration of follow-up for all pts was 27.0 mo (0.1-38.4). Pembro + axi improved OS (HR, 0.68 [95% CI, 0.55-0.85]; P< 0.001; 24-mo OS rate, 74% vs 66%) vs sunitinib. Median (95% CI) OS was not reached with pembro + axi and was 35.7 mo (33.3-NR) with sunitinib. Pembro + axi improved PFS (HR, 0.71 [95% CI, 0.60-0.84]; P< 0.001; 24-mo PFS rate, 38% vs 27%) vs sunitinib. For pembro +axi vs sunitinib respectively, median (95% CI) PFS was 15.4 (12.7-18.9) vs 11.1 mo (9.1-12.5); ORR was 60% vs 40% (P< 0.0001); CR rate was 9% vs 3%; and median DOR was 23.5 mo (range 1.4+ to 34.5+) vs 15.9 mo (range 2.3-31.8+). In general, the pembro + axi benefit was observed in all subgroups tested, including IMDC risk and PD-L1 expression subgroups. Post-hoc landmark analysis at 6-mo showed that pts on pembro + axi with ≥80% target lesion reduction had OS similar to that of pts with CR per RECIST v1.1 based on Kaplan-Meier curves and HR [95% CI] estimates (0.20 [0.05- 0.84] vs. 0.10 [0.01-0.76], respectively) vs pts with 0-30% target lesion reduction. No new safety signals were observed.

Conclusions: Pembro + axi continued to demonstrate superior and durable antitumor activity vs sunitinib in pts with first-line aRCC with a 27-mo median follow up; no new safety signals were observed. Clinical trial information: NCT02853331.

Abstract 5003: Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma.

Eric Jonasch, Frede Donskov, Othon Iliopoulos et al.

Results: As of December 6, 2019, 61 pts were enrolled; median (range) age was 41 years (19-66) and most pts were male (52.5%) and had ECOG PS of 0 (82.0%). The most common lesions outside the kidney (non-RCC tumors) were CNS hemangioblastomas (80.3%) and pancreatic lesions (50.8%). Median (range) duration of treatment was 9.9 mo (1.9-18.2) and 95.1% of pts remain on therapy. Three pts discontinued (AE, n = 1; death [fentanyl toxicity], n = 1; pt decision, n = 1). There were 17 confirmed responses (ORR, 27.9% [95% CI, 17.1-40.8%]) and 8 (13.1%) unconfirmed (documented at 1 timepoint and to be confirmed at subsequent timepoint) responses; all responses were PRs. Of 61 pts, 53 (86.9%) had decrease in size of target lesions. In 17 pts with confirmed response, median (range) DOR was not reached (2.1-9.0 mo) and median (range) TTR was 5.5 mo (2.7-14.0). Responses were also observed in CNS, retinal, and pancreatic lesions. Median PFS was not reached; 12-mo PFS rate was 98.3%. Treatment-related AEs (TRAEs) occurred in 96.7% of pts, mostly grade 1 (44.3%) or grade 2 (42.6%) and primarily (≥20%) anemia (83.6%; considered an on-target- toxicity), fatigue (49.2%), and dizziness (21.3%). Grade 3 TRAEs occurred in 9.8% of pts, primarily fatigue (4.9%) and anemia (3.3%). There were no grade 4 or 5 TRAEs. One pt discontinued because of a TRAE (dizziness).

Conclusions: MK-6482 showed promising efficacy and tolerability in pts with VHL-associated ccRCC and responses in other VHL-related lesions. These data support further investigation of MK- 6482 in VHL disease. Clinical trial information: NCT03401788.

Abstract 5006: Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment- naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260).

Michael B. Atkins, Opeyemi Jegede, Naomi B. Haas et al.

Results:123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Median age 65 (range 32-86 years); 72% male. IMDC favorable 30 (25%), intermediate 79 (65%) and poor risk 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). 117 pts are currently evaluable for response. RECIST defined ORR was: 34 (29.3%)[CR 5 (4.3%), PR 29 (24.8%)], SD 47 (40.2%), PD 36 (30.7%). ORR by irRECIST was 35%. ORR by IMDC was: favorable 12/29 (41.4%), intermediate/poor 22/87 (25.3%) and for SARC 6/22 (27.3%). Median DOR is 13.8 (10.9, NA) mo. Median PFS is 7.4 (5.5, 10.9) mo. 110 pts remain alive. 60 pts (54 PD, 6 pSD) to date were potentially eligible for salvage nivo/ipi (Part B), but 28 did not enroll due to symptomatic PD (17), grade 3-4 toxicity on nivo (8), other (3). 27 of 32 Part B pts are currently evaluable for efficacy and 30 for toxicity. Best response to nivo/ipi was PR (11%), SD (30%), PD (59%). ORR by irRECIST was 19%. Grade 3-5 Treatment-related AEs (TrAE) were seen in 35/123 (28)% on nivo with 1 death due to respiratory failure. Grade 3-4 TrAE were seen in 10/30 (33%) on nivo/ipi with 0 deaths. Correlative studies are pending.

Conclusions:Nivo monotherapy is active in treatment naïve ccRCC across all IMDC groups. Toxicity is consistent with prior nivo studies. Salvage treatment with nivo/ipi after nivo monotherapy was feasible in 53% of pts with PD/pSD, with 11% responding. Clinical trial information: NCT03117309.

Abstract 5007: FRACTION-RCC: Innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell

Toni K. Choueiri, Harriet M. Kluger, Saby George et al

Results:46 pts were randomized to NIVO+IPI. Pts had 0 (n = 1), 1 (n = 10), 2 (n = 12), 3 (n = 10), or ≥4 (n = 13) prior lines of therapy. All pretreated pts had prior anti-PD-(L)1-, none had prior anti- CTLA-4- therapy, and 37 had prior TKI-based therapy; 45 pts progressed on anti-PD-(L)1 as the most recent therapy. Most pts had clear cell aRCC (n = 44). After a median study follow-up of 8.9 months, ORR was 15.2%; no pts achieved complete response and 7 achieved partial response. DOR ranged from 2–19+ months (n = 7); 5 pts had ongoing response. Six of 7 responders had received ≥2 prior lines of therapy. Any-grade treatment-related adverse events (AEs) were reported in 36 pts (78.3%; fatigue, rash [both 19.6%], and diarrhea [17.4%] were most common). Grade 3–4 treatment- related AEs were reported in 13 pts (28.3%; diarrhea [8.7%], ↑amylase and ↑lipase [both 6.5%] were most common). Treatment-related immune-mediated AEs of any grade were reported in 22 pts (47.8%; rash [19.6%], diarrhea [17.4%], and ↑alanine aminotransferase [8.7%]). No treatment-related deaths were reported. Updated and expanded results with an additional 3 months of follow-up will be presented.

Conclusions:These results suggest that NIVO+IPI may provide durable partial response in some pts with prior progression on checkpoint inhibitors, including some heavily pretreated pts. The safety profile of NIVO+IPI in FRACTION pts was similar to historic data in aRCC with this combination. Clinical trial information: NCT02996110.

Abstract 5008: Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC).

Chung-Han Lee, Amishi Yogesh Shah, James J Hsieh et al.

Results:104 pts were enrolled. At data cutoff (January 12, 2020), 71 (69%) pts were still on study treatment. Most pts had ≥2 prior anticancer regimens (58%). 91 of 104 pts were evaluable for response at Week 12 (13 pts NE at Week 12); 46 of 91 pts achieved a confirmed partial response for an ORR of 51% (Table). Median progression-free survival (PFS) was 11.7 months and median duration of response (DOR) was 9.9 months. The most common treatment-related adverse events (TRAEs) were fatigue (49%), diarrhea (44%), proteinuria (37%), hypertension (31%), nausea (31%), dysphonia (29%), stomatitis (29%), and arthralgia (27%). There was 1 grade 5 TRAE (upper gastrointestinal hemorrhage). 43% of pts required dose reduction and 12% of pts discontinued treatment due to TRAEs. Response and safety data will be updated to include all pts evaluable at an April 9, 2020 cut-off.

Conclusions:LEN + PEMBRO demonstrated promising antitumor activity in pts with mccRCC with disease progression following ICI therapy. No new safety signals were detected. Efficacy outcomes by investigator review per irRECIST. Clinical trial information: NCT02501096.

Abstract 5020: Biomarker analysis and updated clinical follow-up of preoperative ipilimumab (ipi) plus nivolumab (nivo) in stage III urothelial cancer (NABUCCO).

Nick Van Dijk, Alberto Gil Jimenez, Karina Silina et al.

Results:After a median FU of 15.6 months, 2 pts relapsed (both non-pCR); 1 of these 2 pts died of metastatic disease. Tumors showing complete response (CR, for biomarker analysis defined as pCR, CIS or pTa) had a significantly higher tumor mutational burden than non-CR tumors. CR to ipi+nivo was independent of baseline CD8 T-cell presence. There was no difference between CR and non-CR tumors in baseline immune gene signatures, such as interferon gamma and T-effector signatures. Surprisingly, exploratory gene expression analysis revealed that non-CR was associated with a baseline B cell immune signature, particularly immunoglobulins and genes involved in B cell receptor signaling. CD20 positive cells (by mIF) and presence of tertiary lymphoid structures (TLS) at baseline were also associated with non-CR. Upon treatment with ipi+nivo, early and mature TLS increased significantly in responding tumors. A subset of pts showed CR in the bladder, but non-CR in a local LN tumor focus. WES revealed that these LN metastases were genetically different from the primary tumor bulk.

Conclusions:At 15.6 months follow-up, recurrence after pre-operative ipi+nivo was low. Pathological complete response was not restricted to tumors exhibiting preexisting T cell immunity. Clinical trial information: NCT03387761.

Abstract 5024: Association of gene expression with clinical outcomes in patients with renal cell carcinoma treated with pembrolizumab in KEYNOTE-427.

David F. McDermott, Jae-Lyun Lee, Frede Donskov et al.

Results:Patient characteristics for this analysis were comparable to the overall population. In cohort A, T-cell–inflamed GEP (n = 78) was statistically significantly associated with a better ORR (P = 0.021; AUROC = 0.65) but not PFS (P = 0.116). No other TME canonical signatures showed a correlation with ORR or PFS. ORR was estimated for mutations (Table).

Conclusions:RNA-sequencing–based, T-cell–inflamed GEP was associated with ORR in patients with clear cell renal cell carcinoma receiving first-line pembrolizumab. Precision was limited by sample size for estimating ORR by specific gene mutation status. Evaluation of tissue-based biomarkers in larger studies are planned. Biomarker analyses from patients in cohort B will also be presented. Clinical trial information: NCT02853344.

Abstract 5061: Association of neutrophil to lymphocyte ratio (NLR) with efficacy from JAVELIN Renal 101.

Mehmet Asim Bilen, Brian I. Rini, Robert J. Motzer et al.

Results:In the avelumab + axitinib arm, patients with < median NLR (N = 217) had longer observed PFS (stratified HR, 0.85; 95% CI, 0.634, 1.153) and longer observed OS (stratified HR, 0.51; 95% CI, 0.300, 0.871) than patients with ≥ median NLR (N = 217). The ORR was 57.1% in patients with < median NLR vs 47.5% in patients with ≥ median NLR, with complete response in 5.5% vs 1.4%. Multivariate analysis showed that low NLR was associated with longer PFS and OS by treating baseline NLR as either a continuous variable or a binary variable (dichotomized by median).

Conclusions:Low NLR was associated with better observed treatment outcomes in patients with aRCC who received avelumab + axitinib. Clinical trial information: NCT02684006.

Abstract 5080: Axitinib plus pembrolizumab in patients with advanced renal cell carcinoma: Long-term efficacy and safety from a phase Ib study.

Michael B. Atkins, Igor Puzanov, Elizabeth R. Plimack et al.

Results:At data cut-off date (July 3, 2019), median OS was not reached; 38 (73.1%) patients were alive. 14 (26.9%) patients had died, none were related to treatment. The probability of being alive was 96.1% (95% CI 85.2–99.0) at 1 year, 88.2% (95% CI 75.7– 94.5) at 2 years, 82.2 % (95% CI 68.5– 90.3) at 3 years, and 66.8 % (95% CI 49.1–79.5) at 4 years. Median PFS was 23.5 (95% CI 15.4–30.4) months. Median duration of response was 22.1 (95% CI 15.1–not evaluable) months. Median time on treatment with the combination AXI/pembro was 14.5 months (n=52), median time on pembro after AXI discontinuation was 9.0 months (n=10), and median time on AXI after pembro discontinuation was 7.5 months (n=11). After stopping study treatment, 22 patients received subsequent systemic therapy, including nivolumab and cabozantinib (n=6 each). Grade 3/4 AEs were reported in 38 (73.1%) patients. 20 (38.5%) patients discontinued either drug due to AEs: 17 (32.7%) patients discontinued AXI, and 13 (25.0%) patients discontinued pembro with 10 (19.2%) discontinuing both drugs. Dose reduction of AXI due to AEs was reported in 16 (30.8%) patients. The most common AEs reported were diarrhea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%), and dysphonia (48.1%). Increased alanine aminotransferase and aspartate aminotransferase occurred in 44.2% and 36.5% of patients, respectively. With this longer follow-up, there were no cumulative AEs or new AEs. OS by IMDC risk group will be presented.

Conclusions:In patients with advanced RCC with almost 5 years of follow-up, the combination of AXI/pembro continues to demonstrate clinical benefit with no new safety signals. Clinical trial information: NCT02133742.

Abstract 5082: Immune infiltration and angiogenesis as markers of outcome in the post- nephrectomy setting: Transcriptomic data from patients receiving placebo on a randomized phase III trial (PROTECT).

A. Ari Hakimi, Martin H Voss, Fengshen Kuo et al.

Results:Tumors from 236 patients were available for analysis. Overall, 37% developed metastatic recurrence and 81% were alive at last follow up. On univariate analysis increasing tumor stage, higher UISS score, and angiogenesis/myeloid subgroups (high – H and low – L) were associated with worse DFS and OS (all p values <0.05). On multivariate analysis TME subgroups remained significant for worse DFS and OS (Table).

Conclusions:Microenvironmental subgroups stratified into angiogenic and myeloid expression profiles carry independent prognostic significance and should be further explored to guide future biomarker-directed adjuvant trials. Clinical trial information: NCT01235962.