Key PD-1/PD-L1 Phase 3 Trials: The Competitive Landscape
| Trial | Regimen | Sponsor | Setting | Status |
|---|---|---|---|---|
| NCT04613219 | Pembrolizumab + chemo vs SoC | Merck | MSS colorectal cancer | Active Phase 3 |
| NCT04940299 CheckMate-9DX | Nivolumab + Ipilimumab vs SoC | BMS | Hepatocellular carcinoma (adjuvant) | Active Phase 3 |
| NCT03298893 | Durvalumab + Olaparib vs SoC | AstraZeneca | NSCLC with DDR deficiency | Active Phase 3 |
| NCT04901715 | Cemiplimab + chemotherapy vs chemo | Regeneron | Cervical cancer | Active Phase 3 |
| NCT04760444 | Dostarlimab + chemo vs chemo | GSK | MMR-deficient endometrial cancer | Active Phase 3 |
The PD-1/PD-L1 Landscape: Market Maturity and Differentiation Pressure
Checkpoint inhibition has progressed through three phases of clinical development: single-agent activity in biomarker-selected populations (2011-2016), combination with chemotherapy as first-line therapy (2017-2022), and now the perioperative frontier — neoadjuvant and adjuvant settings where cure is the goal rather than disease control.
Seven agents are now FDA-approved:
- Pembrolizumab (Keytruda, Merck): 40+ indications across melanoma, NSCLC, HNSCC, esophageal, gastric, cervical, endometrial, CRC (MSI-H), TMB-high solid tumors, biliary, HCC, TNBC, and more. The broadest oncology franchise in history.
- Nivolumab (Opdivo, BMS): Approved across melanoma, NSCLC, RCC, classical Hodgkin lymphoma, HNSCC, MSI-H CRC, gastric, HCC, MPM, ESCC, and adjuvant settings. CheckMate trial program has produced 30+ approvals.
- Atezolizumab (Tecentriq, Roche): PD-L1 inhibitor; approved in NSCLC (IMpower series), TNBC, HCC, small cell lung cancer. First PD-L1 inhibitor approved in NSCLC (2016).
- Durvalumab (Imfinzi, AstraZeneca): NSCLC (PACIFIC, consolidation after concurrent chemoradiation), SCLC (CASPIAN), HCC (HIMALAYA, with tremelimumab), biliary tract (TOPAZ-1). POSEIDON data with tremelimumab in 1L NSCLC represents AZ's direct challenge to pembrolizumab+chemo KEYNOTE-189.
- Avelumab (Bavencio, Pfizer/EMD Serono): Merkel cell carcinoma and urothelial carcinoma maintenance. More limited footprint than peers.
- Cemiplimab (Libtayo, Regeneron): CSCC, BCC, NSCLC, and cervical cancer. Regeneron's growing position in IO.
- Dostarlimab (Jemperli, GSK): dMMR endometrial cancer and dMMR solid tumors. GSK's primary IO asset.
The PD-L1 assay fragmentation creates ongoing treatment complexity. Four different IHC assays (22C3, 28-8, SP142, SP263) with different scoring systems (TPS vs CPS vs IC score) are used across approved pembrolizumab, nivolumab, atezolizumab, and durvalumab indications — making cross-trial comparison and treatment selection harder than it should be.
Where the Battles Are Being Fought Now
Checkpoint inhibition has saturated the metastatic setting across most solid tumors. The remaining active battlegrounds involve resistant tumor types, earlier treatment lines, and combination strategies:
- MSS colorectal cancer (the great unmet need): MSI-H/dMMR CRC (approximately 4% of mCRC) responds dramatically to pembrolizumab. But MSS CRC (96% of patients) does not — despite aggressive combinations including anti-VEGF, MEK inhibitors, LAG-3 inhibitors, and CTLA-4 agonists. Every combination tried in Phase 3 has failed. This remains the most significant unmet need in solid tumor IO.
- SCLC: Atezolizumab+carboplatin+etoposide (IMpower133) and durvalumab+platinum-etoposide (CASPIAN) both received approvals, but OS benefit is modest. The SCLC IO market is fragmented — no single regimen has won clearly — creating BD opportunity for novel combination partners.
- Perioperative NSCLC: KEYNOTE-671 (pembrolizumab neoadjuvant + adjuvant in resectable NSCLC) established pembro as the first perioperative immunotherapy approval. CHECKMATE 77T (nivolumab) and AEGEAN (durvalumab) are competing in the same space.
- Biomarker-defined subgroups: MSI-H/dMMR in endometrial (dostarlimab GARNET, pembrolizumab KEYNOTE-158), HRD in ovarian, KRAS G12C in NSCLC (combination with AMG-510). The precision oncology + IO convergence is the major growth area.
Notable competitors outside the US: sintilimab (Innovent/Lilly), budigalimab (AbbVie), and tislelizumab (BeiGene/Novartis) are all PD-1 inhibitors with major Phase 3 datasets, primarily developed in China but expanding globally. These represent future biosimilar-pricing pressure even before formal biosimilar entry.
Next-Generation Checkpoint Strategies: What's Working and What Isn't
PD-1/PD-L1 blocking antibodies work by releasing the "brake" on T-cells exhausted by chronic antigen exposure. Multiple other brakes exist, and the field has invested heavily in targeting them:
- CTLA-4 (ipilimumab, tremelimumab): The original checkpoint inhibitor (ipilimumab, 2011). Combined with PD-1 inhibition (nivolumab+ipi = Opdualag in melanoma; durvalumab+tremelimumab = IMJUDO in HCC and NSCLC), CTLA-4 blockade remains clinically validated but with a higher toxicity burden. CheckMate-227 established nivo+ipi in high TMB NSCLC. The combination's irAE profile — colitis, endocrinopathies, hepatitis — limits use vs pembro+chemo in many patients.
- LAG-3 (relatlimab): Relatlimab (BMS) + nivolumab = Opdualag, approved 2022 in unresectable or metastatic melanoma. This is the only approved LAG-3 inhibitor. Phase 3 data in other tumors (NSCLC, TNBC) has been mixed. LAG-3 marks exhausted T-cells co-expressing PD-1 — the combination in LAG-3+/PD-1+ T-cell-rich tumors is the hypothesis. Mechanism is validated; tumor-type selection remains the challenge.
- TIGIT: Multiple large Phase 3 failures (tiragolumab SKYSCRAPER-01, vibostolimab, domvanalimab). The mechanistic hypothesis — that blocking TIGIT on T-cells combined with PD-1 blockade produces additive or synergistic T-cell activation — has not translated to clinical benefit at the Phase 3 level despite positive Phase 2 data. Most companies have substantially deprioritized TIGIT programs. Whether TIGIT is permanently dead or requires better patient selection is actively debated.
- TIM-3: Earlier stage than LAG-3. AstraZeneca (cobolimab), BMS (sabatolimab), and Novartis all have TIM-3 programs in Phase 2. TIM-3 is expressed on exhausted CD8+ T-cells and may be particularly relevant in hematologic malignancies (sabatolimab in AML).
The takeaway for pharma BD: the second-generation checkpoint combination market is crowded, the signals are mixed, and patient selection via tissue biomarkers is not solved. Programs with novel combination rationale — particularly IO + targeted therapy combinations (e.g., pembro + KRAS inhibitor, pembro + PARP inhibitor in HRD populations) — have more differentiated positioning than IO + IO doublets.
Related Pages
- Non-Small Cell Lung Cancer Clinical Trials
- Melanoma Clinical Trials
- Triple-Negative Breast Cancer Clinical Trials
- CAR-T Cell Therapy Clinical Trials
- Bispecific Antibody Clinical Trials
- Antibody-Drug Conjugate (ADC) Clinical Trials
- HER2-Targeted Cancer Clinical Trials
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Start Free Trial →Frequently Asked Questions
How many PD-1/PD-L1 inhibitor clinical trials are currently active?
As of March 2026, there are more than 1,255 trials on ClinicalTrials.gov involving PD-1 or PD-L1 checkpoint inhibitors — the largest drug class in oncology trial activity. NCI sponsors 118 active trials, M.D. Anderson Cancer Center 63, AstraZeneca 51 (durvalumab programs), Merck 41 (pembrolizumab), Roche 26, BMS 15 (nivolumab), and Regeneron 13 (cemiplimab). Pembrolizumab alone has received more than 40 FDA approvals across tumor types, making it the most broadly approved drug in history.
What biomarkers predict response to PD-1/PD-L1 checkpoint inhibitors?
The four established predictive biomarkers are: (1) PD-L1 expression by IHC (TPS or CPS, with different assays per drug creating algorithm complexity); (2) MSI-H/dMMR — the strongest pan-tumor predictor, approved across tumor types; (3) TMB (tumor mutational burden) — correlates with neoantigen load, approved for pembrolizumab in TMB-high solid tumors; and (4) specific oncogenic mutations where checkpoint activity combines with targeted therapy. Patients with MSI-H tumors respond dramatically to PD-1 inhibition regardless of tumor type.
Why has TIGIT failed in clinical trials despite early promise?
Multiple large Phase 3 TIGIT trials have failed — including Roche's tiragolumab + atezolizumab in SKYSCRAPER-01 for PD-L1-high NSCLC. The positive Phase 2 signals did not hold at Phase 3 scale. Current thinking is that TIGIT inhibition may require specific T-cell phenotypes not captured by PD-L1 or TMB screening, and that TIGIT-expressing regulatory T-cells may be the relevant target rather than effector T-cells. Most companies have substantially deprioritized TIGIT programs, though the mechanism is not considered permanently invalidated.