Clinical interventions¶

Confidently known¶

human Ipilimumab inaugurated the durable-survival-plateau paradigm (Hodi 2010 NEJM)¹; 20–26% of metastatic melanoma patients on a long-term OS plateau extending to 10+ years. The nivolumab phase I (Topalian 2012)² extended this proof into anti-PD-1 and showed activity across multiple histologies (melanoma, NSCLC, RCC).
human Pembrolizumab first-line for NSCLC with PD-L1 TPS ≥50% is standard of care (KEYNOTE-024)³; 5-year OS benefit confirmed despite ~66% crossover.
human PD-1 + CTLA-4 combination improves PFS over single-agent PD-1 in advanced melanoma (CheckMate 067)⁴; largest relative benefit in PD-L1-negative tumors; ~55% grade 3/4 TRAEs. Durable OS benefit at 6.5+ years.
human Pembrolizumab in dMMR/MSI-H solid tumors — basis of the first tissue-agnostic FDA approval (Le 2017)⁵ — and 1L pembrolizumab in dMMR mCRC (KEYNOTE-177)⁶ are standards of care. But KEYNOTE-177 has complications (see contradictions).

Study	N	Feature	Effect	95% CI / p	Method
Hodi 2010	n=676 (phase 3, previously-treated HLA-A*0201⁺ metastatic melanoma)	ipilimumab 3 mg/kg (± gp100) vs gp100	OS HR ipi+gp100 vs gp100 mOS 10.0 vs 6.4 mo (HR 0.68); ipi vs gp100 HR 0.66	p<0.001 (ipi+gp100) / p=0.003 (ipi alone)	phase 3 RCT
Topalian 2012	n=296 (melanoma 94, NSCLC 76, RCC 33, and others; phase 1 dose-escalation)	nivolumab (BMS-936558) across histologies; PD-L1 IHC predictive	ORR / PD-L1 association melanoma 28%, NSCLC 18%, RCC 27%; PD-L1⁺ vs PD-L1⁻ ORR 36% vs 0%	p=0.006 (PD-L1 association)	phase 1 dose-escalation + PD-L1 IHC
Reck 2016	n=305 (KEYNOTE-024 phase 3, 1L advanced NSCLC, PD-L1 TPS ≥50%, EGFR/ALK-wt)	PD-L1 TPS ≥50% (pembrolizumab vs platinum doublet)	PFS HR mPFS 10.3 vs 6.0 mo; HR 0.50	95% CI 0.37–0.68, p<0.001	PD-L1 IHC 22C3
Larkin 2015	n=945 (CheckMate-067 phase 3, untreated metastatic melanoma)	nivo+ipi vs nivo vs ipi monotherapy	PFS HR (combo vs ipi) mPFS 11.5 vs 6.9 vs 2.9 mo; HR 0.42 combo vs ipi (HR 0.57 nivo vs ipi)	—	phase 3 RCT
Le 2017	n=86 (phase 2 expansion across 12 tumor types, MMR-deficient tumors)	MMR deficiency	ORR 53% (CR 21%)	—	MMR IHC / MSI testing + pembro phase 2
André 2020	n=307 (KEYNOTE-177 phase 3, treatment-naive dMMR/MSI-H mCRC)	1L pembrolizumab vs 5-FU-based chemotherapy	PFS HR mPFS 16.5 vs 8.2 mo; HR 0.60	95% CI 0.45–0.80, p=0.0002	phase 3 RCT

human KEYNOTE-177 PFS was biphasic and OS did not reach significance. Pembrolizumab underperformed chemotherapy in the first ~6 months (~29% primary progression), then crossed over and doubled median PFS (16.5 vs 8.2 mo, HR 0.60). Final OS was HR ~0.74, not statistically significant, largely because chemo patients could cross over to pembrolizumab on progression. Interpretation: dMMR is necessary-but-not-sufficient in mCRC; ~30% have primary resistance that is not currently predictable.
human bTMB retrospective signal did not confirm prospectively. Gandara 2018⁷ showed bTMB-high enriched atezolizumab benefit retrospectively in POPLAR/OAK; B-F1RST prospectively did not confirm. bTMB has not achieved broad regulatory adoption.
human Pan-tumor TMB-high pembrolizumab approval is debated. The FDA's tissue-agnostic approval for TMB ≥10 mut/Mb (based on KEYNOTE-158) has been controversial as some high-TMB histologies (certain gliomas) show limited benefit. TMB thresholds are assay- and context-specific.
human TGF-β bifunctional / pathway-blocking combinations have disappointed despite compelling Mariathasan/Tauriello biology (see TME exclusion). Bintrafusp alfa INTR@PID lung 037 discontinued 2021.
human IDO + pembrolizumab failed (ECHO-301) despite compelling preclinical rationale. Cautionary tale for future metabolic-ICI combinations.

Study	N	Feature	Effect	95% CI / p	Method
Gandara 2018	POPLAR (test) + OAK (validation) NSCLC atezolizumab	blood TMB ≥16 mut/Mb (FoundationACT ctDNA)	PFS HR (atezo vs docetaxel) HR ~0.65 at bTMB ≥16 in OAK	—	ctDNA (FoundationACT)

human 8-gene k-TSP classifier + mucinous histology identifies a ~15% subgroup of dMMR/MSI-H mCRC with extreme benefit from anti-CTLA-4 addition (HR 0.10 for 24-month PFS; 72.2% vs 13.8%)⁸. Retrospective across non-randomized comparisons; prospective validation called for. If it holds, would resolve the decade-long question of when to add ipi to nivo-class regimens in dMMR CRC.
human LOAd703 + atezolizumab in anti-PD-1-refractory melanoma (n=24) shows biomarker-level rescue of ICI-responsive signatures⁹. Small single-arm; needs randomized confirmation.

Study	N	Feature	Effect	95% CI / p	Method
Ambrosini 2026	n=163 (pooled across 2 independent dMMR/MSI-H mCRC cohorts)	Cluster A + mucinous histology (15% biomarker-positive subgroup)	24-mo PFS / HR (Combo vs Mono) 72.2% vs 13.8%; HR 0.10	95% CI 0.02–0.39, p<0.001	8-gene k-TSP classifier + histology
Grauers 2026	n=24 (single-arm phase I/II, anti-PD-1-refractory stage IV melanoma)	intratumoral LOAd703 (CD40L/4-1BBL oncolytic adenovirus) + atezolizumab	immune-signature biomarker increased DC markers, T-cell infiltration, EM CD8⁺; decreased circulating Tregs	—	multi-parameter flow + TME transcriptomics

human ATOMIC phase 3 (NEJM 2026): adjuvant atezolizumab + mFOLFOX6 in stage III dMMR colon cancer, HR 0.50¹⁰. 3-year DFS 86.3% vs 76.2%; 40.9-month median follow-up; grade 3/4 AEs 84.1% vs 71.9%. OS not yet mature. Extends ICI benefit to the adjuvant dMMR setting. A large new patient population will now experience prolonged ICI exposure.
human Anti-TIM-3 (TQB2618) + anti-PD-1 penpulimab in PD-1-pretreated classical Hodgkin lymphoma achieves 52% ORR in 21 evaluable patients¹¹. Salvage signal in a setting where re-engaging checkpoint biology was not expected.

Study	N	Feature	Effect	95% CI / p	Method
Sinicrope 2026	n=712 (phase 3 ATOMIC (NCT02912559), stage III dMMR colon cancer)	atezolizumab + mFOLFOX6 vs mFOLFOX6 alone	3-yr DFS / HR 86.3% vs 76.2%; HR 0.50	95% CI 0.35–0.73, p<0.001	phase 3 RCT
Hong 2026	n=21 (phase Ib (NCT05400876), PD-1-pretreated relapsed/refractory cHL)	anti-TIM-3 TQB2618 + anti-PD-1 penpulimab	ORR 52% (1 CR, 10 PR); grade ≥3 TRAE 24%	—	phase Ib clinical trial

1L NSCLC PD-L1 ≥50%: single-agent pembrolizumab is standard; KEYNOTE-024 data are durable.
Metastatic melanoma: nivolumab + ipilimumab vs single-agent PD-1 is an individualized decision based on disease burden, PD-L1 status, and patient fitness for immune-related toxicity; the combination's largest relative benefit is in PD-L1-negative disease.
dMMR mCRC: pembrolizumab 1L is standard, but counsel patients about the ~30% early-progression risk and reassess imaging at ~2 months.
Stage III dMMR colon cancer (post-resection): ATOMIC brings adjuvant atezolizumab + FOLFOX into the standard-of-care conversation; await OS maturation and guideline uptake.
Hyperprogression on anti-PD-1: a contested phenomenon. Definitions vary; natural history and pseudoprogression confound the literature. Not actionable today as a management decision.