Background

Pembro showed antitumor activity and manageable toxicity in R/M HNSCC in an extended phase 1b study. KEYNOTE-040 (NCT02252042) was a global, open-label, phase 3 study of pembro vs SOC for R/M HNSCC.

Methods

Eligible pts with SCC of the oral cavity, oropharynx, hypopharynx, or larynx who had recurrence or PD after a platinum-containing regimen were randomized 1:1 to pembro 200 mg Q3W for 24 mo or investigator choice of standard doses of methotrexate (M), docetaxel (D), or cetuximab (C). Randomization was stratified by ECOG PS (0 vs 1), HPV status (p16 positive vs negative), and PD-L1 tumor proportion score (TPS) (≥50% vs < 50%). Treatment was given until confirmed PD or intolerable toxicity. Primary end point was OS in the ITT population. Key secondary end points were OS in pts with PD-L1 combined positive score (CPS) ≥1% and PFS and ORR in the ITT and CPS ≥1% populations. Prespecified efficacy boundary for OS in the ITT population was one-sided P = .0175.

Results

495 pts enrolled: 247 were assigned to pembro, 248 to SOC (65 M, 110 D, 73 C). After median follow-up of 7.3 mo, 8.9% of pts remained on pembro, 0.9% on SOC. Pembro prolonged OS in the ITT population, but the difference did not achieve statistical significance (HR 0.81, one-sided P = .0204; Table). There was no difference in PFS (Table). ORR was higher with pembro (Table). Pembro outcomes were improved in pts with PD-L1–expressing tumors (Table). 12.5% of pts in the SOC arm received subsequent immunotherapy, potentially impacting OS. Grade 3-5 drug-related AE incidence was 13.4% with pembro and 36.3% with SOC; 1.6% and 0.9%, respectively, died of drug-related AEs.

Table:

LBA45_PR OS, PFS, and ORR in KEYNOTE-040

Conclusions

Pembro provided an 19% reduction in the risk of death over SOC in pts with R/M HNSCC, although the prespecified efficacy boundary was not reached; subsequent immunotherapy in the SOC arm may have confounded OS analysis. Greater differences in OS, PFS, and ORR favoring pembro were seen in patients with PD-L1 expressing tumors.

Clinical trial identification

ClinicalTrials.gov number NCT02252042, originally posted Sep 25, 2014; EudraCT number 2014-001749-26, originally issued 1-Aug-2014

Legal entity responsible for the study

Merck & Co., Inc.

Funding

Merck & Co., Inc.

Disclosure

E.E. Cohen: Advisory board member for Human Longevity Inc., Merck, and CARsgen Therapeutics. Receiving honoraria from Merck, Pfizer, Celgene, AstraZeneca, Bristol-Myers Squibb, Merck Serono, Amgen, Apexigen, and Vigilant Biosciences. K.J. Harrington: Advisory board member, speakers\' bureau, and honoraria: MSD, AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer Research funding: MSD, AstraZeneca. C. Le Tourneau: Advisory board: MSD, AstraZeneca, Bristol-Myers Squibb, Amgen. Honoraria: Merck Serono, AstraZeneca, Bristol-Myers Squibb. Travel expenses: Bristol-Myers Squibb, MSD, Merck Serono. J. Dinis: Advisory board: Roche, PharmaMar, Bristol-Myers Squibb, Merck Serono. Research funding: Boehringer Ingelheim. Honoraria: Bristol-Myers Squibb, Merck Serono. Travel expenses: Bristol-Myers Squibb, PharmaMar. L. Licitra: Consulting or advisory role: Eisai, Bristol-Myers Squibb, MSD, Merck-Serono, Boehringer Ingelheim, Debiopharm, Jobi, Novartis, AstraZeneca, Bayer, Roche, Amgen, DOBI. Travel: Merck-Serono, Debiopharm, DOBI, Bayer, Amgen. M-J. Ahn: Advisory board member and honoraria: AstraZeneca, Merck, Lilly, Bristol-Myers Squibb, Roche A. Soria: Advisory board: Bristol-Myers Squibb, Roche, Novartis, Incyte. Speakers\' bureau: Roche, Novartis, MSD, Bristol-Myers Squibb. Travel: Roche, MSD, Bristol-Myers Squibb. J-P. Machiels: Advisory board: MSD (uncompensated), AstraZeneca, Debio, Nonbiotix, Innate. Research funding: Novartis, Bayer, Janssen. N. Mach: Advisory board: MSD, Bristol-Myers Squibb, Amgen. Honoraria: Bristol-Myers Squibb R. Mehra: Consulting: Genentech. B. Burtness: Advisory board member: Merck, Boehringer Ingelheim, AstraZeneca, Amgen Research funding (to institution): Merck, Advaxis, Bristol-Myers Squibb. Travel expenses: Boehringer Ingelheim. Y. Wang, A.J. Tuozzo, R. Swaby: Employment and stock ownership: Merck & Co., Inc. D. Soulieres: Advisory board member and research funding: Merck & Co.

Background

Treatment responses to immune checkpoint inhibitors may occur after initial radiologic evidence of progression. In CheckMate 141 (NCT02105636), a randomized phase 3 study in patients (pts) with R/M SCCHN, nivolumab (nivo) significantly prolonged overall survival (OS) vs single-agent of investigator’s choice (HR = 0.70 [97.73% CI: 0.51, 0.96]). We provide a biomarker analysis and updated clinical outcomes of nivolumab treatment beyond first disease progression.

Methods

This analysis is based on a Sept 2016 database lock (minimum follow-up: 11.4 mo). Progression was assessed per RECIST 1.1. Treatment beyond first progression was permitted in the nivo arm for pts who met protocol defined criteria. Pts without progression or tumor assessment to determine progression were excluded. Immune cell phenotyping was conducted by flow cytometry for pts with samples available for both day 1 (D1) and D43 of treatment, and associated with clinical response status.

Results

Of 240 pts randomized to nivo, 146 (61%) experienced progression. Among them, 62 (42%) received ≥1 dose of nivo after progression (TBP group), and 84 (58%) were not treated beyond progression (NTBP group). Median OS was 12.7 mo (95% CI: 9.7, 14.6) in the TBP group. After initial progression, 15 (24%) pts in the TBP group had a reduction in target lesion size, with >30% reduction in 3 pts. Of these 15 pts, 8 were HPV+, 4 had PD-L1 ≥1%, and 5 had >20% increase in target lesion at first progression. Frequencies of grade 3–4 treatment-related adverse events were similar in the TBP and NTBP groups. At D1 and D43, the percentage of CD8+ T cells in peripheral blood for TBP pts (n = 5) was similar to that for responders (n = 15), which was significantly higher vs NTBP pts (n = 9). At D1, the percentage of PD-1+ CD8+ effector T cells was significantly lower in responders and TBP pts vs NTBP pts. At D1, TBP pts, similar to responders, had a significantly lower PD-1+ Treg percentage vs NTBP pts.

Conclusions

Nivo treatment beyond progression in some pts with R/M SCCHN was tolerable and associated with tumor size reductions. Certain immune cell profiles in the TBP group appear similar to those of responders.

Clinical trial identification

NCT02105636

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

R. Haddad: Grants to my institution from Bristol-Myers Squibb, Merck, Celgene, Pfizer, and AstraZeneca; personal fees from Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Celgene, and Eisai. G. Blumenschein Jr: Research grants from: Merck, AstraZeneca, Celgene, AbbVie, Benentech, Xcovery, Novartis, Bayer, Bristol-Myers Squibb, GlaxoSmithKline; Consulting fees from: Bristol-Myers Squibb, Bayer, Celgene, Clovis, AbbVie, Ariad, AstraZeneca, Merck. J. Fayette: Personal fees from Bristol-Myers Squibb and AstraZeneca. J. Guigay: Research grants to my institution from: Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, and Merck Serono. A.D. Colevas: Research grants outside of the submitted work from: Bristol-Myers Squibb, IRX Therapeutics, Threshold Pharmaceuticals, AstraZeneca, and Innate Pharma. L. Licitra: Consulting/grants to institution/travel fees: Merck-Serono; Consulting/grants to institution: Eisai, MSD, Merck-Serono, Boehringer Ingelheim, Novartis, AstraZeneca, Roche; Consulting/travel fees: Bayer, Debiopharm, Sobi; Consulting: Bristol-Myers Squib. S. Kasper: Personal fees for advisory board participation from Bristol-Myers Squibb. E.E. Vokes: Consulting/advisory role with: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Genentech, Leidos, Merck, Regeneron, Serono, Takeda, VentiRx. N.F. Saba: Advisory board participation/personal fees: Bristol-Myers Squib, Lilly, Merck; Member of DSMC/personal fees: Pfizer. M. Tahara: Ad board/Research funding: Ono Pharmaceuticals, MSD, AstraZeneca, Pfizer; Ad board/Lecture honorarium: Bristol-Myers Squib, Bayer; Lecture honorarium/Research funding: Eisai; Lecture honorarium: Otsuka; Research funding: Boehringer-Ingelheim, Novartis, NanoCarrier. M. Monga, M. Lynch: Bristol-Myers Squibb employee. L. Li: Bristol-Myers Squibb employee. J.W. Shaw: Bristol-Myers Squibb employee and shareholder. M.L. Gillison: Honoraria, Consulting, Travel, Accommodations, and Expenses: Celgene, Lilly, Amgen, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Merck; Research funding to my institution: Bristol-Myers Squibb, Merck, AstraZeneca, Kyowa. K.J. Harrington: Honoraria: AstraZeneca, Bristol-Myers Squib, Merck, MSD, Pfizer; Advisory Board membership: AstraZeneca, Bristol-Myers Squib, Merck, MSD, Pfizer; Research Grants: MSD. R.L. Ferris: Research funding: AstraZeneca/MedImmune, Bristol-Myers Squibb, VentiRx; Clinical Trial: AstraZeneca/MedImmune, Bristol-Myers Squibb, Merck; Advisory Board: Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, Lilly, Marck, Pfizer. All other authors have declared no conflicts of interest.

Background

R/M HNSCC patients (pts) who have progressed on platinum-based chemotherapy have a poor prognosis and limited therapeutic options. Programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) are frequently up-regulated in several tumor types, including HNSCC. The global, single-arm, Phase 2 HAWK study (NCT02207530) evaluated the anti-PD-L1 immunotherapy durvalumab as monotherapy in PD-L1 high pts with R/M HNSCC who have failed platinum-based chemotherapy.

Methods

Immunotherapy-naïve pts aged ≥18 years with confirmed PD-L1 high protein expression (≥25% of tumor cells [TCs] using the Ventana SP263 assay) who had progression or recurrence during/after 1 platinum-based regimen for R/M HNSCC received durvalumab 10 mg/kg IV every 2 weeks up to 12 months or until progression, starting another anticancer therapy, consent withdrawal, or unacceptable toxicity. The primary endpoint was objective response rate (ORR; blinded independent central review, RECIST v1.1); secondary endpoints included progression-free survival (PFS) and overall survival (OS).

Results

As of Sept 26, 2016, 112 pts from 12 countries had received treatment (median age 60 years, 71.4% male, 34.7% human papillomavirus [HPV]+, and 61.6% current/former smokers). Median durations of treatment and follow-up were 3.45 and 5.96 months, respectively. Among evaluable pts (n = 111), ORR was 13.5% (95% CI 7.8–21.3) overall and 26.5% (95% CI 12.9–44.4) and 7.9% (95% CI 2.6–17.6) for HPV+ and HPV- pts, respectively; among responders (n = 15), 12 (80%) had an ongoing response at data cutoff (DCO). 35 pts (31.5%) had stable disease ≥8 weeks. Median PFS was 2.3 months (95% CI 1.9–3.7) and 34 pts (30.4%) were alive at DCO (OS data were immature). The incidence of grade ≥3 treatment-related adverse events (AEs) was 9.8% and no treatment-related AEs led to death. 88 pts (78.6%) discontinued initial study treatment, 65 (58%) due to progressive disease and 10 (8.9%) due to all-causality AEs.

Conclusions

Durvalumab demonstrated promising antitumor activity with an acceptable safety profile in PD-L1 high pts with R/M HNSCC, supporting its potential use, and the opportunity to improve efficacy, in combination therapy.

Clinical trial identification

NCT02207530 (release date: August 1, 2014)

Legal entity responsible for the study

AstraZeneca PLC

Funding

AstraZeneca PLC

Disclosure

D. Zandberg: PI at UMGCCC for trials by Medimmune, AstraZeneca, Merck, Macrogenics, Bristol-Myers Squib, Gliknik. A. Algazi: UCSF receive research funding on my behalf from AstraZeneca, Merck, Bristol-Myers Squib, MedImmune, Acerta, OncoSec, Novartis. A. Jimeno: Consultant for AstraZeneca, one presentation at research meeting in January 2016 J.S. Good: Corporate sponsored research: AstraZeneca and Honoraria: Eisai, Bayer, Sirtex, BTG J. Fayette: Honoraria: Bristol-Myers Squib, AstraZeneca. N. Ready: Consultant: AstraZeneca, Bristol-Myers Squib, Merck, Celgene, Abbvie and Honoraria: Bristol-Myers Squib, Abbvie. P.M. Clement: Speakers’ Bureau and Corporate sponsored research: AstraZeneca. T. Goswmi, A. Jarkowski, J.M. Armstrong: Employee & Shareholder of AstraZeneca. K. Asubonteng: Employee & Shareholder of AstraZeneca. Corporate sponsored research: AstraZeneca. G. Melillo: Employee & Shareholder of AstraZeneca. R. Mesía: Speakers’ Bureau: Merck, SL and Consultant: Merck, SL, MSD, Bayer, AstraZeneca, Bristol. All other authors have declared no conflicts of interest.

Background

Checkpoint inhibitors have shown efficacy in pts with recurrent and/or metastatic head and neck cancer (HNC). Atezolizumab (atezo; anti–PD-L1) inhibits binding of PD-L1 to PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Here, we examine single-agent safety and clinical activity of atezo in pts with advanced HNC.

Methods

Pts with HNC received atezo IV q3w (15 or 20 mg/kg or 1200 mg) in a Ph Ia study (NCT01375842). Pts were initially enrolled non-selectively (n = 10); once PD-L1 was identified as a potential biomarker, pts were selected by PD-L1 status (> 5% PD-L1 expression on IC [IC2/3]; centrally evaluated by VENTANA SP142 IHC assay, n = 22). HPV status was assessed by PCR. Treatment was originally for 16 cycles or up to 1 y; pts were subsequently treated until loss of clinical benefit. Primary endpoint was safety; tumor responses were evaluated by RECIST v1.1.

Results

As of 31 Dec 2016, with follow-up of ≥ 14 mo, 32 pts were safety and efficacy evaluable. 84% were male; 66% had ECOG PS of 1. Median age was 62 y (range, 32-78 y), pts were heavily pre-treated (53% had ≥ 2 prior lines of therapy) and 66% were current/previous tobacco users. Most common primary tumor sites were oropharynx (50%), oral cavity (22%) and nasopharynx (19%). Median treatment duration was 3.4 mo; 21/32 pts (66%) had a treatment-related AE. 3 pts (9%) had Gr 3 treatment-related AEs (tumor lysis syndrome, hyponatremia, pruritus, colitis). 1 pt (3%) had Gr 4 treatment-related cardiac tamponade. No Gr 5 treatment-related AEs were seen. In all pts (IC0/1, n = 7; IC2/3, n = 25), confirmed ORR was 22%, mPFS was 2.6 mo (range, 0.5-48.4 mo) and mOS was 6.0 mo (range, 0.5-51.6+ mo). Clinical activity by PD-L1 subgroups is shown in the Table. Preliminary analyses indicate that there was no association between HPV status and clinical outcomes.

Conclusions

In advanced HNC, atezo was well tolerated. Encouraging response and long-term survival were seen independently of PD-L1 IHC or HPV status and warrant further investigation.Table:

1044O Clinical Activity per RECIST v1.1 in PD-L1 Subgroups

Clinical trial identification

NCT01375842

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

F.S. Braiteh: Speaking and consulting fees received from Genentech. A.S. Balmanoukian: Speaker\'s bureau for Merck, Bristol-Myers Squib, Genentech, and AstraZeneca. F.S. Hodi: Consultant Merck, Bristol‐Myers Squibb, Genentech, EMD Serono, Amgen; Research support to institution from Bristol‐Myers Squibb. B. Liu, L. Molinero, X. Shen: Genentech employee and stock. C. O\'Hear: Genentech employee and Roche stock. All other authors have declared no conflicts of interest.