Vol 18, No 2 2020
ASCO20 Annual Meeting - Abstracts
Top Picks by our editor, Robert A. Figlin
Abstract 5001 https://meetinglibrary.asco.org/record/185941/abstract
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, Rustem Gafanov, Tom Waddell, Dmitry Nosov, Frédéric Pouliot, Denis Soulieres, Bohuslav Melichar, Ihor Vynnychenko, Sergio Jobim Azevedo, Delphine Borchiellini, Raymond S. McDermott, Jens Bedke, Satoshi Tamada, Lina Yin, Mei Chen, L. Rhoda Molife, Michael B. Atkins, Thomas Powles; Fox Chase Cancer Center, Philadelphia, PA;. Vanderbilt-Ingram Cancer Center, Nashville, TN; Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine, Dnipro, Ukraine; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; The Christie NHS Foundation Trust, Manchester, United Kingdom; Central Clinical Hospital With Outpatient Clinic, Moscow, Russian Federation; CHU of Quebec and Laval University, Quebec City, ON, Canada; Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada; Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; Sumy State University, Sumy Regional Oncology Center, Sumy, Ukraine; Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Centre Antoine Lacassagne, Université Côte d’Azur, Nice, France; Adelaide and Meath Hospital and University College Dublin, Dublin, Ireland; Eberhard-Karls University Tübingen, Tübingen, Germany; Osaka City University Hospital, Osaka, Japan; Merck & Co., Inc., Kenilworth, NJ; MSD UK, London, United Kingdom; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute, and Queen Mary University of London, London, United Kingdom
Research Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Background: The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) demonstrated that pembrolizumab (pembro) + axitinib (axi) significantly improved OS, PFS, and ORR vs sunitinib as first-line therapy for advanced RCC (aRCC) at the first pre-planned interim analysis (minimum study follow-up of 7 mo). Updated analyses are presented here.
Methods: Treatment-naive patients (pts) with clear cell aRCC, KPS ≥70%, and measurable disease (RECIST v1.1) were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for up to 35 doses + axi 5 mg orally BID or sunitinib 50 mg orally QD on a 4-wk on/2-wk off schedule until progression, toxicity, or withdrawal. Randomization was stratified by IMDC risk (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs rest of world). Primary end points were OS and PFS. Secondary end points were ORR, DOR, and safety. All P values are nominal. A post-hoc exploratory analysis was done to evaluate association of depth of response (maximum reduction from baseline in sum of diameters of target lesions) and OS using landmark analysis up to 6 mo after randomization.
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 https://meetinglibrary.asco.org/record/185945/abstract
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, Wendy Kimryn Rathmell, Vivek Narayan, Benjamin Louis Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Sarah J. Welsh, Sanjay Thamake, Eric Kristopher Park, Naseem J. Zojwalla, Rodolfo F. Perini, W. Marston Linehan, Ramaprasad Srinivasan; The University of Texas MD Anderson Cancer Center, Houston, TX; Aarhus University Hospital, Aarhus, Denmark; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; Vanderbilt University, Nashville, TN; University of Pennsylvania, Philadelphia, PA; University of Utah, Salt Lake City, UT; Hôpital Européen Georges-Pompidou, Paris, France; University of Michigan, Ann Arbor, MI; University of Pittsburgh, Pittsburgh, PA; Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; Peloton Therapeutics Inc., Dallas, TX, a subsidiary of Merck & Co., Inc., Kenilworth, NJ; Merck & Co., Inc., Kenilworth, NJ; National Cancer Institute, Bethesda, MD; Center for Cancer Research, National Cancer Institute, Bethesda, MD
Research Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Background: Patients (pts) with Von Hippel-Lindau disease (VHL) are at risk for several cancers, including clear cell renal cell carcinoma (ccRCC). Inactivation of VHL results in constitutive activation of the HIF-2α transcription factor, which drives tumor growth. MK-6482, a potent, selective, small molecule HIF-2α inhibitor, has shown favorable safety and antitumor activity in a phase 1/2 study. We present initial results of the open-label phase 2 study of MK-6482 for treatment of VHL-associated ccRCC (NCT03401788).
Methods: Adult pts with a pathogenic germline VHL variation, measurable localized/nonmetastatic ccRCC, no prior systemic anticancer therapy, and ECOG PS of 0/1 received MK-6482 120 mg orally once daily until progression, intolerable toxicity, or investigator/pt decision to withdraw. Primary end point was ORR of VHL-associated ccRCC tumors per RECIST v1.1 by independent radiology review. Secondary end points were DOR, time to response (TTR), PFS, and safety and tolerability.
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 https://meetinglibrary.asco.org/record/185946/abstract
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, David F. McDermott, Mehmet Asim Bilen, Charles G. Drake, Jeffrey Alan Sosman, Robert S. Alter, Elizabeth R. Plimack, Brian I. Rini, Michael E. Hurwitz, David J. Peace, Sabina Signoretti, Catherine J. Wu, Paul J. Catalano, Hans J. Hammers; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Dana Farber Cancer Institute, Boston, MA; Penn Medicine Abramson Cancer Center, Philadelphia, PA; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; Herbert Irving Comprehensive Cancer Center, New York, NY; Vanderbilt University Ingram Cancer Center, Nashville, TN; Northern New Jersey Cancer Center, Englewood, NJ; Fox Chase Cancer Center, Philadelphia, PA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Yale School of Medicine, New Haven, CT; University of Illinois at Chicago, Chicago, IL; Department of Pathology, Brigham and Women's Hospital, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
Research Funding: Bristol Meyers Squibb
Background: Nivolumab (nivo) is FDA approved for pts with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment naïve pts with IMDC intermediate and poor risk RCC. Little information is available on the efficacy and toxicity of nivo monotherapy in treatment naïve RCC or the efficacy of nivo/ipi salvage therapy in pts with tumors resistant to initial nivo monotherapy.
Methods: Eligible pts with treatment naïve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg) /ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mo) prior to study entry and prior to Part B. Pathology specimens will be analyzed by immunohistochemistry, quantitative immunofluorescence, WES and RNAseq with results linked to clinical outcome.
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 https://meetinglibrary.asco.org/record/185939/abstract
FRACTION-RCC: Innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell
Toni K. Choueiri, Harriet M. Kluger, Saby George, Scott S. Tykodi, Timothy M. Kuzel, Ruth Perets, Suresh Nair, Giuseppe Procopio, Michael Anthony Carducci, Vincent Castonguay, Edmund Folefac, Chung-Han Lee, Sebastien J. Hotte, Wilson H. Miller, Shruti S. Saggi, David Gold, Robert J. Motzer, Bernard Escudier; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Yale School of Medicine and Smilow Cancer Center, Yale New Haven Hospital, New Haven, CT; Roswell Park Cancer Institute, Buffalo, NY; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; Rush University Medical Center, Chicago, IL; Rambam Health Care Campus, Haifa, Israel; Lehigh Valley Health Network, Allentown, PA; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; Hotel Dieu de Quebec, Quebec, QC, Canada; The Ohio State University Comprehensive Cancer Center, Division of Medical Oncology, Columbus, OH; Memorial Sloan Kettering Cancer Center, New York, NY; Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada; Jewish General Hospital, McGill University, Montreal, QC, Canada; Bristol-Myers Squibb, Princeton, NJ; Gustave Roussy, Villejuif, France
Research Funding: Bristol-Myers Squibb
Background: The immuno-oncology (I-O) combination nivolumab + ipilimumab (NIVO+IPI) is approved for first-line (1L) and NIVO is approved for second-line treatment post TKI therapy in aRCC. The open-label, randomized, phase 2 Fast Real-Time Assessment of Combination Therapies in Immuno-Oncology (FRACTION-RCC; NCT02996110) platform study has an adaptive design allowing rapid evaluation of I-O therapies, including NIVO+IPI or other investigational combinations. This FRACTION analysis reports preliminary outcomes with NIVO+IPI in aRCC pts after progression on checkpoint inhibitor therapy.
Methods: All pts, except 1, had previously received and progressed on checkpoint inhibitor treatment. Pts received NIVO+IPI (NIVO 3 mg/kg + IPI 1 mg/kg Q3W ×4, then after 6 weeks, NIVO 480 mg Q4W), up to 2 years or until progression, toxicity, or protocol-specified discontinuation. Primary endpoints were confirmed objective response rate (ORR; per investigator using RECIST v1.1), duration of response (DOR), and progression-free survival probability at week 24. Safety outcomes were reported.
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 https://meetinglibrary.asco.org/record/186053/abstract
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, Arpit Rao, Alvaro Pinto, Mehmet Asim Bilen, Allen Lee Cohn, Christopher Di Simone, David R. Shaffer, Regina Girones Sarrio, Sara Gunnestad Ribe, Jane Wu, Emmett V. Schmidt, Rodolfo F. Perini, Peter Kubiak, Alan D. Smith, Robert J. Motzer; Memorial Sloan Kettering Cancer Center, New York, NY; MD Anderson Cancer Center, University of Texas, Houston, TX; Washington University School of Medicine, St. Louis, MO; Masonic Cancer Center, University of Minnesota, Minneapolis, MN; Hospital Universitario La Paz, Madrid, Spain; Winship Cancer Institute of Emory University, Atlanta, GA; Rocky Mountain Cancer Center, Denver, CO; Arizona Oncology Associates, Tucson, AZ; New York Oncology Hematology, Albany, NY; Medical Oncology Service, Hospital Universitari i Politècnic La FE, Valencia, Spain; Sorlandet Hospital Kristiansand, Kristiansand, Norway; Eisai Inc., Woodcliff Lake, NJ; Merck & Co., Inc., Kenilworth, NJ; Eisai Ltd., Hatfield, United Kingdom
Research Funding: Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA
Background: LEN, a multikinase VEGFR inhibitor, plus everolimus is approved for advanced RCC after prior VEGF-targeted therapy. PEMBRO, an anti-PD-1 antibody, plus axitinib is approved as first-line therapy of advanced RCC. We report phase 2 results of the RCC cohort of a phase 1b/2 trial (Study 111/KEYNOTE-146) of LEN + PEMBRO in patients (pts) who progressed after ICI therapy.
Methods: We performed a multicenter, open-label study of pts with mccRCC, who previously had disease progression by RECIST (confirmed ≥ 4 weeks later) during or following ICI therapy. Pts had measurable disease by immune-related RECIST, and ≥ 1 prior therapy. Pts received LEN 20 mg orally once daily plus PEMBRO 200 mg IV every 3 weeks until disease progression or toxicity. Tumor assessments were performed every 6 weeks (until week 24), then every 9 weeks. The primary endpoint was objective response rate (ORR) at Week 24 by irRECIST.
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 https://meetinglibrary.asco.org/record/186065/abstract
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, Kees Hendricksen, Laura Smit, Jeantine De Feijter, Maurits L van Montfoort, Annegien Broeks, Yoni Lubeck, Karolina Sikorska, Thierry N. Boellaard, Pia Kvistborg, Daniel J Vis, Erik Hooijberg, Ton Schumacher, Maries van den Broek, Lodewyk FA Wessels, Christian U. Blank, Bas W.G. van Rhijn, Michiel Simon Van Der Heijden; The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Institute of Experimental Immunology, University Hospital Zurich, Zurich, Switzerland; Netherlands Cancer Institute (NKI-AVL), Amsterdam, Netherlands; Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Netherlands Cancer Institute-The Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Statistics, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; The Netherlands Cancer Institute (NKI), Amsterdam, Netherlands; University of Zurich, Zurich, Switzerland; Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
Research Funding: BMS
Background: Encouraging pathological complete response (pCR) rates were observed in trials testing neoadjuvant pembrolizumab or atezolizumab in urothelial cancer (UC). In cT3-4N0 tumors, pCR to atezolizumab was only 17% and restricted to tumors showing characteristics of preexisting T cell immunity. In NABUCCO, we aimed to increase response to pre-operative checkpoint blockade, particularly in high risk patients (pts), by combining ipi plus nivo in stage III UC. We previously reported pCR in 46% and downstaging to no remaining invasive disease in 58% (ESMO2019). Here, we present biomarker analyses and updated clinical follow-up (FU) data.
Methods:Twenty four stage III (cT3-4aN0 or cT2-4aN1-3) UC pts who were unfit to receive cisplatin-based chemotherapy or refused, were treated with ipi 3 mg/kg (day 1), ipi 3 mg/kg + nivo 1 mg/kg (day 22), and nivo 3 mg/kg (day 43), followed by resection. The primary endpoint was feasibility (resection < 12 weeks). Efficacy (pCR), safety and biomarker analysis were secondary endpoints. Whole-exome sequencing (WES) was done on baseline tumor samples and local lymph node (LN) metastases showing no response. RNA-seq and multiplex immunofluorescence (mIF) for immune cell markers were done pre- and post-therapy.
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 https://meetinglibrary.asco.org/record/186062/abstract
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, Scott S. Tykodi, Georg A. Bjarnason, James M. G. Larkin, Rustem Gafanov, Mark D. Kochenderfer, Jahangeer Malik, Alexandr Poprach, Sabina Signoretti, Razvan Cristescu, Raluca Andreia Predoiu, Andrey Loboda, Yiwei Zhang, Qing Zhao, Alexandra Snyder, Charles Schloss, Rodolfo F. Perini, Michael B. Atkins; Dana-Farber Cancer Center, Harvard Medical School, Boston, MA; University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; Aarhus University Hospital, Aarhus, Denmark; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada; The Institute of Cancer Research, London, United Kingdom; Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation; Oncology and Hematology Associates of Southwest Virginia, Roanoke, VA; Edinburgh Cancer Centre, Western General Hospital, Edinburgh, United Kingdom; Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic; Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Merck & Co., Inc., Kenilworth, NJ; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC
Research Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Background: We assessed the association of baseline RNA-sequencing–based gene expression signatures and DNA alterations with response or resistance to pembrolizumab in patients with advanced renal cell carcinoma in cohorts A (clear cell; n = 110) and B (non-clear cell; n = 165) of the phase 2 KEYNOTE-427 study (NCT02853344).
Methods: Using RNA-sequencing, we analyzed the association of gene expression signatures (18-gene T-cell–inflamed gene expression profile [GEP]; 10 non–T-cell–inflamed GEP canonical signatures [angiogenesis, gMDSC, glycolysis, hypoxia, mMDSC, MYC, proliferation, RAS, stromal/EMT/TGFβ, WNT]) quantifying tumor microenvironment elements (TME) with objective response rate (ORR) and progression-free survival (PFS). Canonical signatures were derived from 2 databases (TCGA, Moffit) using an algorithm that included genes based on their correlation to reference signatures in the literature. Signature definitions were finalized before linking to the clinical data, and significance was prespecified at 0.10 given the potential for limited power. Canonical signatures were analyzed through regression testing of response for association with consensus signatures after adjusting for T-cell–inflamed GEP and International Metastatic RCC Database Consortium scores in the model. P values were adjusted for multiplicity. Using whole exome sequencing, we also summarized the association of renal cell carcinoma driver gene mutations with ORR. Clinical data cutoff: Jan 30, 2019.
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 https://meetinglibrary.asco.org/record/186857/abstract
Association of neutrophil to lymphocyte ratio (NLR) with efficacy from
JAVELIN Renal 101.
Mehmet Asim Bilen, Brian I. Rini, Robert J. Motzer, James M. G. Larkin, John B. A. G. Haanen, Laurence Albiges, Lance C. Pagliaro, Eric Voog, Elaine Tat Lam, Nikolai Kislov, Bradley Alexander McGregor, Bo Huang, Alessandra di Pietro, Stan Krulewicz, Toni K. Choueiri; Winship Cancer Institute of Emory University, Atlanta, GA; Vanderbilt University Medical Center, Nashville, TN; Memorial Sloan Kettering Cancer Center, New York, NY; Royal Marsden NHS Foundation Trust, London, United Kingdom; Netherlands Cancer Institute, Amsterdam, Netherlands; Gustave Roussy, Villejuif, France; Mayo Clinic, Rochester, MN; Clinique Victor Hugo, Le Mans, France; University of Colorado Anschutz Medical Campus, Aurora, CO; Yaroslavl Region Clinical Oncological Hospital, Yaroslavl, Russian Federation; Dana-Farber Cancer Institute, Boston, MA; Pfizer, Groton, CT; Pfizer SRL, Milan, Italy; Pfizer, Inc., Collegeville, PA
Research Funding: This study was funded by Pfizer, as part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany.
Background: The phase 3 JAVELIN Renal 101 trial (NCT02684006) in treatment-naive patients with advanced renal cell carcinoma (aRCC) demonstrated significantly improved progression-free survival (PFS; hazard ratio [HR], 0.69; 95% CI, 0.56, 0.84; P < 0.001) and higher objective response rate (ORR; 51.4% vs 25.7%) with avelumab + axitinib vs sunitinib (Motzer RJ, et al. N Engl J Med. 2019;380:1103-15). NLR has emerged as a potential prognostic biomarker in aRCC; elevated NLR is associated with poorer prognosis. Here, we describe the association of NLR with the efficacy of avelumab + axitinib from JAVELIN Renal 101.
Methods: We examined baseline NLR and its association with efficacy outcomes. PFS, best overall response (per blinded independent central review using RECIST 1.1), and overall survival (OS) data from the avelumab + axitinib arm from the first interim analysis of JAVELIN Renal 101 were analyzed (data cutoff, June 20, 2018). Multivariate Cox regression analyses of PFS and OS were also conducted.
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 https://meetinglibrary.asco.org/record/186854/abstract
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, Mayer N. Fishman, David F. McDermott, Daniel C. Cho, Ulka N. Vaishampayan, Saby George, Jamal Christo Tarazi, William Duggan, Rodolfo F. Perini, Kathrine C. Fernandez, Toni K. Choueiri; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Vanderbilt University Medical Center, Nashville, TN; Fox Chase Cancer Center, Philadelphia, PA; Moffitt Cancer Center, Tampa, FL; Beth Israel Deaconess Medical Center, Boston, MA; Perlmutter Cancer Center New York University Langone Health, New York, NY; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Roswell Park Comprehensive Cancer Center, Buffalo, NY; Pfizer Oncology, San Diego, CA; Pfizer Inc., Groton, CT; Merck & Co., Inc., Kenilworth, NJ; Pfizer Inc., Cambridge, MA; Dana-Farber Cancer Institute, Boston, MA
Research Funding: Pfizer
Background: Axitinib (AXI) plus pembrolizumab (pembro) showed superior overall survival (OS), progression-free survival (PFS) and response rate compared with sunitinib in a randomized Phase 3 trial in advanced renal cell carcinoma (RCC). Here, we report long-term efficacy and safety data of the combination AXI/pembro from the Phase 1 trial, with almost 5 years of follow-up.
Methods: 52 treatment-naïve patients with advanced RCC were enrolled between 23 September 2014 and 13 October 2015, and were treated with oral AXI 5 mg twice daily and intravenous pembro 2 mg/kg every 3 weeks. Planned treatment duration was 2 years for pembro and not limited for AXI. Based on International Metastatic Database Consortium (IMDC) criteria, 46.2%, 44.2% and 5.8% of patients were reported as having favourable, intermediate and poor risk.
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 https://meetinglibrary.asco.org/record/187506/abstract
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, Andrew W. Silagy, Mahtab Marker, Albert Reising, John Millholland, Timothy An-thy Chan, Paul Russo, Robert J. Motzer; Memorial Sloan Kettering Cancer Center, New York, NY; Novartis Oncology, East Hanover, NJ; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Novartis Pharmaceutical Corp, East Hanover, NJ
Research Funding: Novartis, Philantropic
Background: Defined stromal and immune features of the tumor microenvironment (TME) have proven relevant for outcomes with systemic therapy in advanced clear cell renal cell carcinoma (ccRCC). We hypothesized that these may matter beyond therapeutic applications and could be relevant much earlier in the disease course. We sought to study the TME in high risk ccRCC patients undergoing definitive surgery.
Methods: Clinical, pathologic, immunohistochemical, and whole-genome microarray data were acquired on 236 out of 769 patients in the Placebo arm of PROTECT trial (NCT01235962 - pazopanib vs placebo). Transcriptomic scores assessing angiogenesis and myeloid infiltration with individual annotations above/below median were used to categorize patients into four groups (angiogenesis high vs. low; myeloid high vs. low). We tested categorical association with disease free (DFS) and overall survival (OS) using logrank testing and assessed interdependence with relevant clinicopathologic variables, including the UCLA Integrated Staging System (UISS) in a cox regression model.
Results: Tumors from236 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.