The CXCR4 chemokine receptor modulates immunosuppressive cell trafficking that can inhibit antitumor immune responses. X4P-001 is a selective, oral CXCR4 antagonist currently in clinical development as a novel therapy for solid tumors, including renal cell carcinoma (RCC). In xenograft models, X4P-001 in combination with axitinib, a VEGF receptor tyrosine kinase inhibitor (TKI), reduced myeloid-derived suppressor cell infiltration and proangiogenic signals and demonstrated greater than additive antitumor activity.
Here we report combined Phase I/II study results for 65 patients (Pts) with advanced RCC treated with 400 mg oral X4P-001 (200 mg BID or 400 mg QD) + 5 mg oral BID axitinib. All Pts had failed at least 1 prior treatment with a TKI, immuno-oncology (IO) agent, or other systemic therapy (2+, n = 49 Pts, 75%; 3+, n = 31, 48%) and had an ECOG performance status of ≤ 2.
The median age was 64 years (range 42-87), and the median treatment duration was 25 weeks (range 1-148). Of the 65 Pts, 12 (18%) remain on combination therapy. The objective response rate (ORR) among the 62 clinically evaluable Pts was 29% (1 complete response; 17 partial responses) and the interim median progression-free survival (mPFS) was 7.4 months. The ORR for Pts receiving immediate prior TKI therapy was 18% (n = 34) and mPFS was 7.4 months. The ORR for Pts receiving immediate prior IO therapy was 61% (n = 18) and mPFS was 11.6 months. Thirteen Pts (20%) were discontinued from the study due to adverse events (AEs) regardless of attribution. The most common (> 20%) treatment-related (TR)AEs of any grade were diarrhea (35 Pts, 54%), decreased appetite (29 Pts, 45%), fatigue (28 Pts, 43%), hypertension (25 Pts, 38%), nausea (17 Pts, 28%), and dysphonia (14 Pts, 22%). The most common TRAEs ≥ Grade 3 were hypertension (14 Pts, 22%) and diarrhea (7 Pts, 11%).
X4P-001 + axitinib is well tolerated in Pts with advanced RCC with a manageable safety profile. In this population, X4P-001 + axitinib demonstrates encouraging mPFS. Therapy is ongoing and updated study results will be presented.
X4P-001-RCCA; Release date: 7 April 2015.
Timothy Henion of Acumen Medical Communications.
X4 Pharmaceuticals.
X4 Pharmaceuticals.
D.F. McDermott: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Exelixix; Honoraria (self), Advisory / Consultancy: Array BioPharm; Honoraria (self), Advisory / Consultancy: Genentech BioOncology; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): Prometheus Laboratories; Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Jounce Therapeutics. T. Ho: Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ipsen Bioscience; Advisory / Consultancy: Roche; Advisory / Consultancy: Cardinal Health; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Novartis. B. Keam: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dohme; Advisory / Consultancy: Genexine; Research grant / Funding (self): Ono Pharmaceutical. R. Joseph: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Array. W. Stadler: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Caremark/CVS; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Sotio; Speaker Bureau / Expert testimony: Applied Clinical Education; Speaker Bureau / Expert testimony: Dava Oncology; Speaker Bureau / Expert testimony: Global Academy for Medical Education; Speaker Bureau / Expert testimony: OncLive; Speaker Bureau / Expert testimony: PeerView; Speaker Bureau / Expert testimony: Vindico; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Astellas (Medivation); Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): X4 Pharmaceuticals. J. Picus: Advisory / Consultancy: NovoNordisk; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): BioClin Therapeutics; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Innocrin Pharmaceuticals; Research grant / Funding (institution): Rexahn Pharmaceuticals; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Tracon Pharmaceuticals; Research grant / Funding (institution): eFFECTOR Therpeutics. Y. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Janssen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Array BioPharm; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer. L. Gan: Full / Part-time employment: X4 Pharmaceuticals. M.B. Atkins: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: Arrowhead; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Genentech-Roche; Advisory / Consultancy: Galactone; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Werewolf; Advisory / Consultancy: Fathom; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Aveo; Advisory / Consultancy: Array; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Ideera; Advisory / Consultancy: Amgen; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Alexion; Advisory / Consultancy: Iovance; Advisory / Consultancy: Newlink. All other authors have declared no conflicts of interest.
Lenvatinib (LEN) is a multikinase VEGFR inhibitor approved for use in combination with everolimus to treat advanced RCC after prior VEGF-targeted therapy. Pembrolizumab (PEMBRO) is an anti-PD-1 antibody. Here, we report results of an interim analysis of the RCC cohort of a phase II trial of LEN + PEMBRO, specifically in patients (pts) who progressed with prior immune checkpoint inhibitor (ICI) therapy.
This is a per-protocol interim analysis of a multicenter, open-label study for pts with mccRCC, ≥1 prior therapy, RECIST disease progression on or following an ICI regimen (confirmed ≥ 4 weeks later), measurable disease, and Eastern Cooperative Oncology Group performance status ≤ 1. Pts received LEN 20 mg/d PO plus PEMBRO 200 mg intravenously Q3W until disease progression or toxicity occurred. Tumor assessments were performed every 6 weeks (until week 24), then every 9 weeks.
At data cutoff (March 29, 2019), the first 33 pts enrolled were followed for ≥12 weeks for response evaluation, and 24 (73%) pts were still on study treatment. The objective response rate was 52%, the disease control rate was 94%, and most pts had tumor shrinkage. Median follow-up time for progression-free survival was 4.2 months. Pt characteristics and efficacy outcomes are summarized in the table. The most common treatment-related adverse events were fatigue (49%), dysphonia (36%), diarrhea (33%), stomatitis (30%), hypertension (24%), dry mouth, nausea, proteinuria, and hand-foot syndrome (21% each). Three (9%) pts discontinued treatment due to adverse events. 1187PD Summary of patient characteristics and efficacy outcomes 30.3% were negative and 33.3% were not available Response duration is based on Kaplan-Meier estimation with 95% CI based on the Greenwood formula using log-log transformation DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; irRECIST, immune-related Response Evaluation Criteria In Solid Tumors; NR, not reached; ORR, objective response rate; PD-L1, programmed death-ligand-1; PFS, progression-free survival; VEGF, vascular endothelial growth factor.Patient Characteristics, n (%) LEN + PEMBRO (n = 33) ECOG performance status 0 18 (54.5) 1 15 (45.5) Prior anticancer regimens 1 prior regimen 14 (42%) >1 prior regimen 19 (58%) Prior VEGF-targeted therapy 26 (78.8%) Prior ICI therapy 33 (100%) PD-1/PD-L1 monotherapy 14 (42.4%) with VEGF agents 9 (27.7%) nivolumab + ipilimumab 7 (21.2%) with other agents 2 (6.1%) PD-L1 positive 12 (36.4)* Investigator assessment of efficacy outcomes by irRECIST LEN + PEMBRO (n = 33) ORR, n (%) 95% CI 17 (51.5) 33.5–69.2 Median PFS (95% CI), months PFS rate, % (95% CI) at: 3 months 6 months 9 months NR (5.6–NR) 93.4 (76.1–98.3) 73.8 (45.7–88.9) 64.6 (34.5–83.5) Median DOR, (95% CI) months NR (4.2–NR) Median follow-up time for DOR, months 6.0 (1.4–7.0) Response duration > = 6 months, n (%)** 80.8 (42.3–94.9)
For the subset of mccRCC pts with disease progression during or following ICI therapy, LEN + PEMBRO demonstrated promising antitumor activity. No new safety signals were detected. The study will continue to full cohort expansion.
NCT02501096; Release date: July 17, 2015.
Tarah M. Connolly, PhD of Oxford PharmaGenesis, Newtown, PA, funded by Eisai Inc.
Eisai Inc.
Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
C. Lee: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Calithera; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Amgen. A.Y. Shah: Honoraria (self), Non-remunerated activity/ies, research: Eisai Inc.; Honoraria (self): Oncology Information Group; Non-remunerated activity/ies, research: EMD Serono; Non-remunerated activity/ies, research: Bristol-Myers Squibb. V. Makker: Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Eisai; Honoraria (self), Non-remunerated activity/ies: Merck; Non-remunerated activity/ies: Lilly; Honoraria (self), Non-remunerated activity/ies: Karyopharm; Non-remunerated activity/ies: Takeda; Non-remunerated activity/ies: Genentech. M.H. Taylor: Research grant / Funding (institution): BioAlta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Array Biopharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: LOXO; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Blueprint; Honoraria (self), Advisory / Consultancy: Arquele; Honoraria (self), Advisory / Consultancy: Novartis. J.J. Hsieh: Honoraria (self): Eisai Inc. A. Pinto Marin: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: EUSA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Clovis; Honoraria (self): Aveo. D.W. Rasco: Research grant / Funding (self): Eisai Inc.; Research grant / Funding (self): Merck. D.E. Stepan: Full / Part-time employment: Formerly of Eisai Inc. C.E. Dutcus: Leadership role, Full / Part-time employment: Eisai Inc. J. Wu: Full / Part-time employment: Eisai Inc. E.V. Schmidt: Full / Part-time employment: Merck & Co Inc. R.F. Perini: Full / Part-time employment: Merck & Co Inc. R.J. Motzer: Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Exelixis; Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Novartis; Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: Incyte. All other authors have declared no conflicts of interest.
Current standard of care (SOC) in 2L GEA, ramucirumab + taxane, has median progression free survival (mPFS) of 4.4 months (m) and median overall survival (mOS) of 9.6 m. Chemotherapy-backbone HER2-targeted agents tested in 2L HER2+ GEA TyTAN and GATSBY studies showed mPFS and mOS ranged 2.4-5.4 months (m), and 7.1-11.2 m. P, in 2L KN061, showed mPFS and mOS of 1.5 m and 9.1 m in GEA pts with PD-L1 CPS >1, and both were lower for PD-L1 all-comers. M is an investigational anti-HER2 Fc-optimized monoclonal antibody that can coordinate activation between innate and adaptive immunity. In pts treated with M+P, we previously reported ORR of 33% in HER-2 IHC-3+ gastric cancer (GC) pts and over 50% in pts with HER-2+/PD-L1+ tumors.
HER2+ PD-L1 unselected 2L GEA pts (N = 86) were enrolled post progression on T-based therapy (tx) and treated with M (15 mg/kg) and P (200 mg) IV Q3wk. We report mPFS and mOS in the overall expansion cohort and in biomarker subgroups including archival PD-L1 and HER2 IHC, ERRB2 ctDNA (prior to 2L tx), and tumor site (GC vs junction [GEJ]).
Median duration of tx was 3.8 m (range 0.7-26.5), with median follow-up 11.3 m (range 1.6-28.6). Pt characteristics (n,%) included: GC 60 (70%), HER2 IHC3+ 68 (79%), PD-L1 CPS>1 32 (37%), ERBB2 ctDNA+ 46 (53%), and MSI-high 1 (1%). In overall GEA pts, mPFS was 3.5 m (95% CI 1.64-4.76), and mOS was 13.9 m (95% CI 9.26-16.82); OS rates at 6/12/18/24 m were 77/57/35/32%, respectively. In GEA HER2 IHC3+ pts, mPFS was 4.5 m (95%CI 2.7-7.5) and mOS was 16.8 m (95%CI 12.23-not reached (NR)). OS rates at 6/12/18/24 m were 85/66/48/44%, respectively; IHC3+ GC (54 [63%]) showed mPFS of 4.7 m (95% CI 2.73-7.49) and mOS NR (95% CI 12.25-NR). IHC3+/ctDNA+ confirmation GEA (38 [44%]) showed mPFS 7.5 m (95% CI 3.5-12.4) and mOS NR (13.27-NR), and IHC3+/ctDNA+ GC (31 [36%]) showed mPFS 5.6 m (95% CI 2.73-8.34) and mOS NR (12.48 – NR). Median PFS and mOS were lower in GEJ: 1.5 m (1.38, 4.34) and 9.2 m (5.26, 15.41), respectively.
In this study, M+P, a chemotherapy-free regimen, demonstrated acceptable tolerability in HER2+ GEA pts post-T, with extension of time-to-event endpoints compared to historical experience with SOC regimens, and checkpoint inhibitors alone.
NCT02689284.
MacroGenics, Inc.
MacroGenics, Inc.
D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Five Prime Therapeutics; Honoraria (self), Speaker Bureau / Expert testimony: Foundation Medicine; Honoraria (self), Advisory / Consultancy: Genentech/Roche; Honoraria (self): GenMab; Honoraria (self): Gritstone Oncology; Honoraria (self), Speaker Bureau / Expert testimony: Guardant Health; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self): NantOmics; Honoraria (self): OncoPlex Diagnostics; Honoraria (self), Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Astellas Pharma. H. Park: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Vertex. H. Uronis: Shareholder / Stockholder / Stock options, Full / Part-time employment: GeneCentric; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution): Advaxis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck. Y. Kang: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): DAE HWA Pharmaceutical; Advisory / Consultancy: Lilly/ImClone; Advisory / Consultancy: Merck/Serono; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Taiho Pharmaceutical; Research grant / Funding (self): LSK Biopharma. M.C.H. Ng: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self), Travel / Accommodation / Expenses: Taiho Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (institution): ASLAN Pharmaceuticals. P. Enzinger: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Taiho Pharmaceutical. K.W. Lee: Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Lilly; Research grant / Funding (institution): ALX Oncology. K.H. Lim: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Vertex. J. Lacy: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: KeyQuest Health; Advisory / Consultancy: Navigant Consulting; Advisory / Consultancy: Sirtex Medical; Travel / Accommodation / Expenses: Lilly. S.H. Park: Advisory / Consultancy: Lilly. K. Huber: Full / Part-time employment: MacroGenics, Inc. A. Wynter-Horton: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Nordstrom: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. T. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Wigginton: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Baughman: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. M. Rosales: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Davidson-Moncada: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy, Research grant / Funding (institution): Green Cross; Advisory / Consultancy: Hanmi; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): MSD Oncology; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Samyang; Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda. All other authors have declared no conflicts of interest.
T + chemo is standard 1st line therapy for HER2+ gastroesophageal adenocarcinoma; however, patients (pts) tend to progress in 6-8 months. Up to 40% show loss of HER2 expression post T, likely underlying the lack of efficacy of anti-HER2 agents in 2nd line therapy. We report here a clinical update and biomarker analysis of an ongoing study in pts receiving M, an anti-HER2 Fc-optimized mAb, plus P in HER2+ GEA pts in post T, 2nd line, chemotherapy-free treatment.
Endpoints described herein are safety, objective response rate (ORR), disease control rate (DCR), archival HER2 IHC level and/or ERBB2 amplification (amp) status pre-M+P in cell free DNA (cfDNA) by NGS (Guardant360), PD-L1 CPS by IHC (22C3 pharmDx), anti-HER2 T- cell immunity by ELISPOT on PBMCs, and NanoString PanCancer IO360™ assay on archival FFPE biopsies.
92 pts (66% GC, 34% GEJ) received 15 mg/kg M + 200 mg P Q3W. 99% were MSS and 43% were PD-L1 + (>1%). Related adverse events ≥grade 3 were 18.5%. Confirmed ORR was 19% with 54% DCR; interestingly, higher response rates occurred in GC vs GEJ (25% vs 7% ORR, p = 0.047 and 64% vs 33% DCR, p = 0.008). A higher proportion of GC vs GEJ cancers was HER2 3+ on archival IHC (90% vs 53%, p = 0.0075), furthermore, a 5.3-fold greater fraction of GC vs GEJ pts showed upregulated tumor ERBB2 RNA expression (p < 0.001). Pts with upregulated tumor ERBB2 RNA expression showed a 3-fold greater frequency of DCR (p = 0.003). While not statistically significant, more GC pts retained HER2+ status post T (62.5% vs 50%) or expressed PD-L1 by IHC (46.3% vs 31.8%); notably, however, the frequency of dual ERRB2 amplified plus PD-L1+ was >6-fold higher in GC vs GEJ (34.7% vs 5.5%, p = 0.03) and associated with 53% confirmed ORR and 82% DCR in GC. GC pts with higher baseline T-cell immunity toward HER2 (p59 class II peptide) had greater probability of ORR (p = 0.005).
In this study, M+P demonstrated tolerability and preliminary evidence of anti-tumor activity as a chemotherapy-free regimen in 2nd line HER2+ GC; biomarker analysis suggests an association with higher expression and retention of HER2 and PD-L1 together with pre-existing anti-HER2 immunity.
NCT02689284.
MacroGenics, Inc.
MacroGenics, Inc.
H. Park: Research grant / Funding (institution): Ambrx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Vertex. H. Uronis: Shareholder / Stockholder / Stock options, Full / Part-time employment: GeneCentric; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution): Advaxis; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck. Y. Kang: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): DAE HWA Pharmaceutical; Advisory / Consultancy: Lilly/Imclone; Advisory / Consultancy: Merck/Serano; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche/Genentech; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): LSK Biopharma. M.C.H. Ng: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Honoraria (self), Travel / Accommodation / Expenses: Taiho Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (institution): ASLAN Pharmaceuticals. P. Enzinger: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Taiho Pharmaceutical. K.W. Lee: Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Lilly; Research grant / Funding (institution): ALX Oncology. S. Rutella: Leadership role: Clinical & Biomarkers Data Sharing Subcommittee, Society for Immunotherapy of Cancer; Research grant / Funding (institution): John and Lucille van Geest Foundation. S.E. Church: Shareholder / Stockholder / Stock options, Full / Part-time employment: NanoString Technologies. J. Nordstrom: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. T. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Yen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. A. Franovic: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. J. Muth: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. M. Rosales: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. J. Davidson-Moncada: Shareholder / Stockholder / Stock options, Full / Part-time employment: MacroGenics, Inc. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy, Research grant / Funding (institution): Green Cross; Advisory / Consultancy: Hanmi; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): MSD Oncology; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Samyang; Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): CKD; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda. D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Five Prime Therapeutics; Honoraria (self), Speaker Bureau / Expert testimony: Foundation Medicine; Honoraria (self), Advisory / Consultancy: Genentech/Roche; Honoraria (self): GenMab; Honoraria (self): Gritstone Oncology; Honoraria (self), Speaker Bureau / Expert testimony: Guardant Health; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): Merck; Honoraria (self): NantOmics; Honoraria (self): OncoPlex Diagnostics; Honoraria (self), Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Astellas Pharma. All other authors have declared no conflicts of interest.
Tumor HP has been suggested to occur in some patients with solid tumors subsequent to PD-1/L1 inhibitor monotherapy; however, reports are based on nonrandomized, single-arm studies. Previous post-hoc analysis of HP with nivo was performed in the phase III ATTRACTION-2 trial, which randomized patients with gastric cancer who received ≥2 prior lines of therapy to nivo or pbo. Using the pbo arm as a surrogate for natural course of disease progression, nivo was not associated with HP at ≥ 20, ≥50, or ≥ 100% tumor growth rates. The current analysis expands this framework to assess HP in patients with extensive disease small cell lung cancer (ED SCLC) in the randomized, pbo-controlled CheckMate 451 trial.
CheckMate 451 was a phase III double-blind study that evaluated maintenance treatment in patients with ED SCLC without disease progression after platinum-based 1L chemotherapy. Patients were randomized to nivo 240 mg, nivo 1 mg/kg + ipilimumab 3 mg/kg, or pbo, within 9 weeks from the last dose of 1L chemotherapy (or ≤ 11 weeks for those receiving PCI or whole brain radiotherapy); HP analysis focused on the nivo (n = 280) and pbo (n = 275) arms. Tumor assessments occurred every 6 weeks for the first 36 weeks, then every 12 weeks until disease progression. HP was calculated as changes in size of the primary lesion (sum of longest diameters [SLD]), as assessed retrospectively among patients who had baseline and ≥1 on-treatment tumor measurement available (nivo, n = 177; pbo, n = 175).
Baseline characteristics were balanced between treatment arms in the analysis population. Median increase in tumor size from baseline to first on-treatment assessment in the maintenance period was 2% with nivo vs 17% with pbo. Compared to the pbo arm, fewer patients on nivo had SLD increases of ≥20% (27% vs 46%), ≥50% (10% vs 22%), and ≥100% (3% vs 6%) at the first on-treatment scan.
In this analysis, nivo was not associated with HP in the pbo-controlled CheckMate 451 trial. These data are consistent with the previous analysis of ATTRACTION-2, suggesting that reports of HP with immunotherapy may reflect some patients’ natural course of disease.
CheckMate 451 trial: NCT02538666.
ONO-4538-12/ATTRACTION-2 trial: NCT02267343.
Stephen Gutkin and Jay Rathi, MA, of Spark Medica Inc, funded by Bristol-Myers Squibb.
Bristol-Myers Squibb and ONO Pharmaceutical Co. Ltd.
Bristol-Myers Squibb and ONO Pharmaceutical Co. Ltd.
M. Reck: Honoraria (self): AbbVie; Honoraria (self): Amgen ; Honoraria (self): AstraZeneca ; Honoraria (self): Boehringer Ingelheim; Honoraria (self): BMS ; Honoraria (self): Celgene; Honoraria (self): Lilly ; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche. Y. Feng: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. H.R. Kim: Honoraria (self), Advisory / Consultancy, Honoraria, consulting or advisory role: AstraZeneca; Honoraria (self), Advisory / Consultancy, Honoraria, consulting or advisory role: Roche; Honoraria (self), Advisory / Consultancy, Honoraria, consulting or advisory role: Boehringer Ingelheim. G. Plautz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. Y. Kang: Advisory / Consultancy: Ono ; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSKBiopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MacroGenics ; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis. T.K. Owonikoko: Research grant / Funding (institution): Novartis, Astellas Pharma, Celgene, Bayer, Stemcentrx, Regeneron, AstraZeneca/MedImmune, AbbVie, G1 Therapeutics, Bristol-Myers Squibb, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea BioTherapeutics, Incyte, Merck; Advisory / Consultancy: Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Heron Pharmaceutical, ARMO Bi; Shareholder / Stockholder / Stock options, Co-founder: Cambium Oncology. P. Nghiem: Honoraria (self), Honoraria for consulting: EMD Serono-Pfizer, Merck, Regeneron-Sanofi; Research grant / Funding (institution): EMD Serono, Bristol-Myers Squibb. J. Sheng: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb.
Immune Checkpoint blockade for the treatment of metastatic melanoma is associated with highly variable clinical outcomes between individuals in terms of both oncological benefit and immune-related adverse events. Early markers of response are urgently sought. Whereas numerous intra-tumoural determinants of sensitivity to immunotherapy are known, the identification of peripheral predictors of response is limited. We aimed to characterize the CD8+ T-cell transcriptomic and clonal changes to treatment across a large cohort of patients in an effort to gain further insight into the peripheral markers of response.
We performed paired-end 75bp read RNA-sequencing to assay the peripheral CD8+ response at baseline and across multiple cycles of treatment (n = 105 patients, 69 controls, 315 separate transcriptomes). We validated identified clonal subsets indicative of response using 10X Chromium single cell sequencing (16 samples, 8 patients), flow-cytometry and targeted PCR.
After adjusting for multiple testing, we identify >5,800 transcripts induced by treatment. These fall into discrete gene modules, with several markedly diverging between combination immunotherapy and anti-PD1 alone. Patients demonstrating a durable radiological response to checkpoint immunotherapy (absence of progression at 6 months) have significantly increased numbers of large peripheral CD8+ circulating clones by day 21 after treatment, compared to non-responders and controls. We replicate this observation in a separately recruited cohort. Large peripheral clones have a distinct gene expression profile, characterized by high expression of CCL5, BCL2L1and NKG7 amongst other genes.
We identify robust and reproducible predictors of 6 month clinical and radiological responses to immune checkpoint blockade in the transcriptomes of peripheral circulating CD8+ T-cells from metastic melanoma patients after 21 days of treatment. These observations can be used to further our understanding of determinants of patient response, and may provide a mechanism for early treatment stratification of patients with a non-favourable peripheral profile.
Oxford Radcliffe Biobank.
Wellcome Trust, Oxford NIHR Biomedical Research Centre, Cancer Research UK.
All authors have declared no conflicts of interest.