Checkpoint Inhibitor Combinations

What to add to an anti-PD-(L)1 backbone when PD-1 blockade alone is not enough: inhibitory checkpoints beyond PD-1 such as LAG-3, TIGIT and TGF-beta, co-stimulatory agonists, and targeted agents paired with immunotherapy to overcome acquired resistance — and whether a second agent improves response or only adds toxicity.

10 articles in this topic

• September 17, 2026JAMA OncologyVERSATILE-002 (Phase 2, nonrandomized)

  HPV16 Vaccine Plus Pembrolizumab Reaches a 34% Response Rate in Checkpoint-Naive Head and Neck Cancer, but 0% After Prior Checkpoint Inhibitor Therapy

  VERSATILE-002 was a phase 2, open-label, multicenter, nonrandomized trial of the HPV16 E6/E7 peptide vaccine PDS0101 combined with pembrolizumab in HPV16-positive recurrent or metastatic head and neck squamous cell carcinoma. 87 patients were treated in two separately analyzed cohorts: immune checkpoint inhibitor (ICI)-naive and ICI-resistant.

• September 15, 2026Clinical Cancer ResearchNCI/ETCTN 10476 (NCT04941287)

  Adding a CD27 Agonist to Checkpoint Blockade Fails to Improve Response in Biliary Tract Cancer

  A randomized phase II trial testing whether the CD27 costimulatory agonist varlilumab, combined with atezolizumab and the MEK inhibitor cobimetinib, could rescue checkpoint-inhibitor activity in previously treated, unresectable biliary tract cancer closed early for futility after a preplanned interim analysis.

• August 28, 2026Clinical Cancer ResearchC-800-01 phase 1b expansion cohort

  Botensilimab Plus Balstilimab Produces Durable Responses and 33% Three-Year Survival in Refractory, Microsatellite-Stable Colorectal Cancer

  An open-label phase 1b expansion cohort within a larger basket study tested Fc-enhanced anti-CTLA-4 antibody botensilimab plus anti-PD-1 antibody balstilimab in 123 patients with microsatellite-stable metastatic colorectal cancer without active liver metastases, most of whom were heavily pretreated.

• September 1, 2026Cancer DiscoveryNCT02706353

  Intratumoral CD40 Agonist Plus Pembrolizumab Yields 50% ORR in Melanoma

  A first-in-human, open-label, single-arm phase I/II trial tested whether an intratumoral CD40 agonist (sotigalimab) added to systemic pembrolizumab could turn immunologically "cold" tumors "hot" in patients with immune-checkpoint-blockade-naive metastatic melanoma.

• July 27, 2026Journal of Clinical OncologyNCT04294810

  SKYSCRAPER-01: Adding Tiragolumab to Atezolizumab Fails to Improve PFS or OS in PD-L1-High NSCLC

  A global, randomized, double-blind, placebo-controlled phase 3 trial (SKYSCRAPER-01) tested whether adding the anti-TIGIT antibody tiragolumab to atezolizumab would improve outcomes over atezolizumab alone in previously untreated, PD-L1-high non-small cell lung cancer (NSCLC).

• August 3, 2026Cancer DiscoveryNCI 18-C-0110 (NCT03554473)

  TGF-β Blockade Plus PD-L1 Inhibition Triggers Hyperprogression in Relapsed Small Cell Lung Cancer

  A single-center, investigator-initiated Phase Ib/II trial (NCI protocol 18-C-0110, NCT03554473) tested bintrafusp alfa — a bifunctional PD-L1/TGF-β fusion protein — alone or with chemotherapy in 37 patients with relapsed small cell lung cancer treated between 2019 and 2022.

• July 30, 2026JAMA OncologyI-SPY2 (NCT01042379)

  Dual PD-1/LAG-3 Blockade Nearly Doubles Complete Response in High-Risk Breast Cancer

  A Phase 2 arm of the adaptive I-SPY2 platform trial (78 patients treated 2020-2021, compared against 350 historical controls) tested adding cemiplimab (anti-PD-1) and fianlimab (anti-LAG-3) to neoadjuvant chemotherapy in high-risk, stage II-III, ERBB2 (HER2)-negative breast cancer.

• July 22, 2026Clinical Cancer ResearchMONETTE (NCT05061134)

  MONETTE Phase II Trial: Ceralasertib Combinations Fall Short in PD-(L)1-Resistant Melanoma

  Randomized (2:1), open-label, international phase II trial of ceralasertib (an oral ATR inhibitor) plus durvalumab versus ceralasertib monotherapy in 151 patients with advanced melanoma that had progressed on prior anti-PD-(L)1 therapy

• July 10, 2026Nature MedicineABTC 1501 (NCT02658981)

  Phase 1 Trial: Anti-LAG-3 Plus Anti-PD-1 Shows Acceptable Safety in Recurrent Glioblastoma

  Open-label, multicenter phase 1 trial (Adult Brain Tumor Consortium, ABTC 1501) of the anti-LAG-3 antibody relatlimab, alone or combined with the anti-PD-1 antibody nivolumab, in 46 patients with first-time recurrent glioblastoma (GBM)

• February 13, 2026Lancet OncologyKEYVIBE-010 (NCT05665595)

  KEYVIBE-010: Adding Vibostolimab to Pembrolizumab Does Not Improve Outcomes in Resected High-Risk Melanoma

  Randomised, double-blind, phase 3 study of 1,402 patients with surgically resected stage IIB–IV cutaneous melanoma across 205 global sites