Background

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.

Methods

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.

Results

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%).

Conclusions

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.

Clinical trial identification

X4P-001-RCCA; Release date: 7 April 2015.

Editorial acknowledgement

Timothy Henion of Acumen Medical Communications.

Legal entity responsible for the study

X4 Pharmaceuticals.

Funding

X4 Pharmaceuticals.

Disclosure

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.

Background

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.

Methods

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.

Results

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.Table:

1187PD Summary of patient characteristics and efficacy outcomes

Conclusions

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.

Clinical trial identification

NCT02501096; Release date: July 17, 2015.

Editorial acknowledgement

Tarah M. Connolly, PhD of Oxford PharmaGenesis, Newtown, PA, funded by Eisai Inc.

Legal entity responsible for the study

Eisai Inc.

Funding

Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

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.

Background

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.

Methods

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]).

Results

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.

Conclusions

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.

Clinical trial identification

NCT02689284.

Legal entity responsible for the study

MacroGenics, Inc.

Funding

MacroGenics, Inc.

Disclosure

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.

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Clinical trial identification

NCT02689284.

Legal entity responsible for the study

MacroGenics, Inc.

Funding

MacroGenics, Inc.

Disclosure

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.

Background

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.

Methods

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).

Results

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.

Conclusions

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.

Clinical trial identification

CheckMate 451 trial: NCT02538666.

ONO-4538-12/ATTRACTION-2 trial: NCT02267343.

Editorial acknowledgement

Stephen Gutkin and Jay Rathi, MA, of Spark Medica Inc, funded by Bristol-Myers Squibb.

Legal entity responsible for the study

Bristol-Myers Squibb and ONO Pharmaceutical Co. Ltd.

Funding

Bristol-Myers Squibb and ONO Pharmaceutical Co. Ltd.

Disclosure

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.

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Legal entity responsible for the study

Oxford Radcliffe Biobank.

Funding

Wellcome Trust, Oxford NIHR Biomedical Research Centre, Cancer Research UK.

Disclosure

All authors have declared no conflicts of interest.