Durvalumab, Tremelimumab Alone or in Combination With Low-Dose or Hypofractionated Targeted Radiotherapy in Metastatic Non-Small Cell Lung Cancer Refractory to Prior PD-1 Therapy: A Multicentre, Open-Label, Randomized, Phase 2 Trial

Background: Patients with non-small cell lung cancer (NSCLC) resistant to PD-1 therapy have poor outcomes. Preclinical studies have suggested that radiotherapy may enhance anti-tumor immunity and promote response to combined PD(L)-1 / CTLA-4 blockade. We therefore investigated combined PD-L1 (durvalumab) and CTLA-4 inhibition (tremelimumab) alone or combined with low-dose or hypofractionated radiation.   Methods: This multicentre, randomized, phase 2 trial by the NCI Experimental Therapeutics Clinical Trials Network was conducted at 18 U.S. sites. 78 patients with metastatic NSCLC were randomized (1:1:1) to durvalumab (1500mg)/tremelimumab (75mg every 4 weeks, 4 cycles) alone or with low-dose (0.5 Gy twice daily x 2 days, 4 cycles) or hypofractionated (8 Gy x 3) radiotherapy followed by durvalumab monotherapy until 52 weeks or progression. The primary endpoint was objective response per RECIST v1.1 excluding irradiated lesions.  Findings: Seventy eight patients were randomized between August 2017 and March 2018. Subjects received a median of 3 prior lines of therapy and 28 weeks of prior PD-1 directed therapy. Adverse events potentially related to therapy occurred in 59 subjects (76%), with grade ≥3 events in 15 (19%) with no differences across arms.  Overall response rate was 10% (95% exact CI: 5-19%), and disease control rate was 30% (95% exact CI: 20-41%) with no differences across arms (p=0.99/0.74, respectively). Median response duration was 10.3 months (95% CI: 1.4 months – not reached). Baseline intratumoral CD4+/PD1+/Ki67+, CD8+/PD1+/Ki67+ and CD8+/PD1+ T-cells were associated with response (p=0.01/0.04/0.03, respectively). Responders also tended to have higher mutational burden (p=0.19) and increases in percent lymphocyte count on treatment (p=0.003). Interpretation: PD-L1/CTLA-4 inhibition was tolerable and led to durable responses or disease control in a subset of PD-(L)1 inhibitor-resistant metastatic NSCLC patients. We didn’t observe benefit to adding concurrent radiotherapy. The predictive value of infiltrating T-cell populations warrants further investigation.  Clinical Trial Registration Details: ClinicalTrials.gov Identifier: NCT02888743 Funding Information: UM1CA186709-01, U24CA224331, and U24CA224316  Declaration of Interests: JDS: Research support paid to the institution: Merck, BMS, Regeneron, Debiopharm Consulting / Scientific Advisory Board / Travel fees: Genentech, Immunitas, Debiopharm, BMS, Nanobiotix, Tilos, AstraZeneca, LEK, Catenion, ACI Clinical, Astellas, Stimit. Expert witness fees. Stock options: Immunitas. Equity: Doximity. AGH: Nothing to declare SR: Nothing to declare KZK: Nothing to declare AL: employee of BMS JT: Nothing to declare YL: Nothing to declare RCB: Nothing to declare RDG: Conflicts: Support for present manuscript: NIH/NCI grant. Grants/contracts (to institution): Pfizer, Mirati, Daiichi Sankyo, Jounce Therapeutics, Helsinn, Bristol Myers Squibb, Merck, Janssen. Consulting fees: Daiichi Sankyo, AstraZeneca, BluePrint Medicines, Pfizer Honoraria: Rockpointe CME, Targeted Oncology, Total Health Conferencing. Travel for meetings: Pfizer, AstraZeneca, Helsinn. CL receives an honorarium for chairing the DSMB for Delcath, Inc. JMH: Advisory boards – Bayer, Merck. Research funding – Merck, Boston biomedical, Treos Bio, Senhwa pharmaceuticals, Bayer, Incyte, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene. JA: Research support from Pfizer, Scientific Advosory Board membership for the Lustgarten Foundation, Stand-up to Cancer, Moleculin Biotech, Bessor Pharma, and Fujifilm; Stock Options from Bessor Pharma, Moleculin Biotech; DSMB membership honoraria from Panbela Therapeutics and the Pancreatic Cancer Action Network. SKJ: Grant funding from Merck, research consultant for Merck, IMX Medical and Syntactx. NU: Consulting: QED, Ipsen, Taiho Inc., Incyte, AstraZeneca, Astellas. Research Funding: Taiho Inc, Eli Lilly, Ipsen, EMD Serono. Long position holdings: Natera, Exact Sciences KS: nothing to declare JMJ: Research funding from Astra Zeneca, BMS, Merck; consulting for Foundation Medicine HP: unpaid ad board for Jounce and Jacobio; research grants from: Ambrx, Amgen, Aprea Therapeutics AB, Array BioPharma, BeiGene, BJ Bioscience, Bristol-Myers Squibb. Daiichi Pharmaceutical, Eli Lilly, Elicio Therapeutics, Exelixis, Genentech, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, MERCK, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, RePare Therapeutics, Seattle Genetics, Synermore Biologics, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Xencor Inc LCV: Advisory board roles for Janssen, BMS, Takeda, and Daiichi Sankyo ES: Nothing to declare HS: Nothing to declare MA: Nothing to declare HL: Nothing to declare CC: Nothing to declare NL: Nothing to declare AJ: Nothing to declare LY: Nothing to declare JA: Nothing to declare LG: Nothing to declare JLW: nothing to declare RHM: Research support: ViewRay, Consulting/Scientific Advisory Board: ViewRay, AstraZeneca. MMA: Consultant for: Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, ArcherDX, Mirati, NextCure, Novartis, EMD Serono Research funding (to institute): AstraZeneca, Lilly, Genentech, Bristol-Myers Squibb SR- SR receives research support from Bristol-Myers-Squibb, Merck, Affimed, and KITE/Gilead. SR is on the SAB of Immunitas Therapeutics and has equity in the company. HXC – no disclosures AMM conflitcts– Research support / Advisory boards: Merck, BMS, Astra-Zeneca, Transgene, Incyte, Trisalus, MultiplexThera, Genentech CJW: CJW holds equity in BioNTech, and receives research funding from Pharmacyclics, Inc. SH: Dr. Hodi reports grants, personal fees and other from Bristol-Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants, personal fees and other from Novartis,personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Aduro, personal fees from Sanofi, personal fees from Pionyr, personal fees from Torque, personal fees from Rheos, personal fees from Bicara, personal fees from Psioxus Therapeutics, other from Pieris Pharmacutical, personal fees from Eisai, personal fees from Checkpoint Therapeutics, personal fees from Idera, personal fees from Takeda, personal fees from Genentech/Roche, personal fees from Bioentre, personal fees from Gossamer, personal fees from Phio, personal fees from Iovance, personal fees from Trillium, personal fees from Catalym, outside the submitted work; In addition, Dr. Hodi has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and uses thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent Therapeuticpeptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides(#20170008962) pending, a patent THERAPEUTIC PEPTIDES Therapeutic Peptides Patent number: 9402905 issued, a patent METHODS OF USING PEMBROLIZUMAB AND TREBANANIB pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued, and a patent ANTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES Publication number: 20170343552 pending. Ethics Approval Statement: The protocol was approved by the central institutional review board cIRB) and then cleared by local institutional review boards of all 18 participating centres. The study was carried out in accordance with the protocol, the principles expressed in the Declaration of Helsinki, and applicable regulatory requirements. All patients provided written informed consent in advance of study-specific procedures.