Skip to content

Lung squamous cell carcinoma — immunotherapy

TL;DR — Checkpoint inhibition transformed metastatic LUSC without requiring a squamous-specific genotype. In CheckMate 017, nivolumab reduced mortality versus docetaxel (HR 0.59, 95% CI 0.44–0.79) and cut grade 3–4 treatment-related toxicity from 55% to 7% (Brahmer 2015, PMID 26028407). KEYNOTE-407 then established first-line pembrolizumab plus carboplatin/taxane: initial OS HR 0.64 (0.49–0.85), with five-year survival 18.4% versus 9.7% for chemotherapy (Paz-Ares 2018, PMID 30280635; Novello 2023, PMID 36735893). Benefit extends across PD-L1 strata, but PD-L1 remains useful for selecting monotherapy in high-expressing tumors; it is an imperfect continuous biomarker, not a binary immune switch (Reck 2016, PMID 27718847). Regimens are not interchangeable: IMpower131 improved PFS but not OS, and adding CTLA-4 blockade to nivolumab in pretreated LUSC did not improve survival (Jotte 2020, PMID 32302702; Gettinger 2021, PMID 34264316). The unresolved problem is post-chemo-IO resistance: empiric CTLA-4 rescue produced 0% response in acquired-resistant and 7% in primary-resistant Lung-MAP cohorts (Leighl 2021, PMID 34429332).

The pivotal sequence

Setting Trial Comparison Key efficacy Safety anchor
Previously treated LUSC CheckMate 017 Nivolumab vs docetaxel OS 9.2 vs 6.0 mo; HR 0.59 (0.44–0.79); ORR 20% vs 9% Grade 3–4 treatment-related AE 7% vs 55%
Untreated metastatic LUSC KEYNOTE-407 Pembrolizumab + carboplatin/taxane vs chemotherapy OS 15.9 vs 11.3 mo; HR 0.64 (0.49–0.85); PFS HR 0.56 Grade ≥3 AE 69.8% vs 68.2%
KEYNOTE-407 long term Same Same 5-y OS 18.4% vs 9.7%; OS HR 0.71 (0.59–0.85) No new major signal
Untreated PD-L1 ≥50% NSCLC KEYNOTE-024 Pembrolizumab vs platinum chemo PFS 10.3 vs 6.0 mo; HR 0.50; ORR 44.8% vs 27.8% Grade 3–5 treatment-related AE 26.6% vs 53.3%
Untreated LUSC IMpower131 Atezolizumab + carboplatin/nab-paclitaxel vs chemo PFS HR 0.71; OS 14.2 vs 13.5 mo, HR 0.88 (0.73–1.05) Grade 3–4 treatment-related AE 68.0% vs 57.5%
Untreated metastatic NSCLC CheckMate 9LA Nivolumab/ipilimumab + 2 chemo cycles vs 4 chemo cycles 5-y OS 18% vs 11%; squamous 18% vs 7% Durable benefit after some toxicity discontinuations

The sequence matters historically. CheckMate 017 tested an IO-naïve post-platinum population; contemporary patients usually receive checkpoint therapy first line, so its comparator and treatment line no longer define the dominant resistance setting.

CheckMate 017: the squamous anchor

CheckMate 017 randomized 272 previously treated advanced-LUSC patients. Nivolumab improved one-year survival from 24% to 42%, response from 9% to 20%, and PFS from 2.8 to 3.5 months. PD-L1 was neither prognostic nor predictive in this trial (Brahmer 2015, PMID 26028407).

The pooled five-year CheckMate 017/057 update found OS 13.4% with nivolumab versus 2.6% with docetaxel and PFS 8.0% versus 0%. Patients progression-free at three years had a 93.0% probability of five-year survival, demonstrating a conditional durable-benefit tail (Borghaei 2021, PMID 33449799).

Patient-reported outcomes in CheckMate 017 favored nivolumab for symptom and health-related quality-of-life trajectories, consistent with the lower severe-toxicity burden (Reck 2018, PMID 29129758). Trial participants had performance status 0–1; frail, autoimmune, transplant, or steroid-dependent populations were underrepresented.

KEYNOTE-407: current first-line backbone

KEYNOTE-407 randomized 559 untreated metastatic-LUSC patients to pembrolizumab or placebo plus carboplatin and paclitaxel/nab-paclitaxel for four cycles, followed by pembrolizumab/placebo to 35 cycles. OS benefit appeared across PD-L1 levels (Paz-Ares 2018, PMID 30280635).

Time point/analysis Pembrolizumab + chemo Chemo Relative effect
Initial median OS 15.9 mo 11.3 mo HR 0.64 (0.49–0.85)
Initial median PFS 6.4 mo 4.8 mo HR 0.56 (0.45–0.70)
Five-year OS 18.4% 9.7% OS HR 0.71 (0.59–0.85)
Five-year PFS effect — — HR 0.62 (0.52–0.74)
Completed 35 pembrolizumab cycles 55 patients — ORR 90.9%; 3-y OS after completion 69.5%

The 35-cycle completer data are conditioned on surviving and responding long enough to finish treatment; they cannot predict outcomes at baseline (Novello 2023, PMID 36735893).

In a pooled PD-L1-negative NSCLC analysis containing 94 pembrolizumab-combination and 99 chemotherapy LUSC patients, chemo-IO improved OS (HR 0.63, 95% CI 0.50–0.79 across histologies). This supports combination therapy despite TPS <1%, but the estimate is pooled and exploratory rather than a standalone LUSC trial (Borghaei 2020, PMID 32914866).

At about five years, a later PD-L1-negative pooled analysis found OS HR 0.64 (0.51–0.79), PFS HR 0.66 (0.54–0.81), and five-year OS 12.5% versus 9.3% across squamous/nonsquamous trials (Gadgeel 2024, PMID 38642841).

Monotherapy selection

Pembrolizumab monotherapy in KEYNOTE-024 improved PFS and OS versus platinum chemotherapy for untreated NSCLC with PD-L1 TPS ≥50% and no EGFR/ALK driver (Reck 2016, PMID 27718847). Atezolizumab likewise improved OS in the highest PD-L1 subgroup of IMpower110 (20.2 vs 13.1 months; HR 0.59), across histologies (Herbst 2020, PMID 32997907).

Cemiplimab monotherapy has durable first-line activity in PD-L1 ≥50% NSCLC, including squamous histology; five-year follow-up supports persistence of benefit (Kilickap 2025, PMID 40118215).

Monotherapy advantage Monotherapy risk
Avoids upfront cytotoxic exposure and neuropathy/myelosuppression Slower or absent response can be dangerous in bulky symptomatic disease
Lower aggregate grade ≥3 toxicity than chemotherapy in pivotal high-PD-L1 trials PD-L1 sampling error and heterogeneity can misclassify
Durable responses in selected tumors Hyperprogression/early progression lacks chemotherapy cytoreduction
Preserves chemotherapy for later use No randomized proof that sequencing is superior to combination in high PD-L1 LUSC

The choice depends on disease tempo, symptoms, tumor burden, comorbidity, and patient priorities—not PD-L1 alone.

Other first-line combinations

Regimen Evidence Interpretation
Atezolizumab + carboplatin/nab-paclitaxel PFS improved; OS not significant in IMpower131 Positive PFS does not substitute for OS; Jotte 2020, PMID 32302702
Nivolumab/ipilimumab + two-cycle chemotherapy Five-year OS 18% vs 11%; squamous 18% vs 7% Durable all-histology option; Reck 2024, PMID 39270380
Same, six-year update Six-year OS 16% vs 10%; squamous 14% vs 5% Benefit persisted across PD-L1 and selected mutation strata; Carbone 2025, PMID 40446626
Cemiplimab + platinum doublet OS/PFS benefit irrespective of histology/PD-L1 All-histology option; Gogishvili 2022, PMID 36008722
Camrelizumab + carboplatin/paclitaxel PFS 8.5 vs 4.9 mo in Chinese LUSC phase III Regional availability; ctDNA clearance exploratory; Ren 2022, PMID 34923163

Cross-trial rankings are unreliable because controls, PD-L1 assays, geography, chemotherapy, follow-up, crossover, and eligibility differ. No head-to-head randomized trial establishes one modern chemo-IO regimen as universally superior in LUSC.

PD-L1: useful, incomplete

PD-L1 tumor proportion score is a continuous, spatially heterogeneous IHC measure. It predicts a higher average response probability to monotherapy, but KEYNOTE-407 benefit across strata and CheckMate 017’s non-predictive finding show it is not required for combination benefit (Brahmer 2015, PMID 26028407; Paz-Ares 2018, PMID 30280635).

Limitation Mechanism Consequence
Spatial heterogeneity Different tumor regions/metastases express different PD-L1 Small biopsy may misclassify
Temporal change Radiation, chemotherapy, inflammation alter expression Archival specimen may not represent current disease
Assay/scoring difference 22C3, SP263, SP142 and tumor/immune-cell algorithms differ Thresholds are regimen-specific
Non-immune oncogenic induction NRF2/other programs can raise PD-L1 High staining does not guarantee inflamed effective immunity
Immune exhaustion Multiple inhibitory checkpoints/Tregs/macrophages coexist PD-1 blockade alone may not restore function

In 624 LUSCs, a transcriptomic “exhausted immune class” comprised approximately 28%–36%, with high PD-L1, regulatory T cells, M2 macrophages, nine co-upregulated checkpoints, and predicted checkpoint resistance. This is retrospective computational evidence, not a clinical test (Yang 2022, PMID 35799269).

TMB and genomic context

LUSC has high mutation burden from tobacco, supplying a mechanistic rationale for checkpoint benefit. Early-stage LUSC showed correlation among PD-L1, TMB, and immune signatures, but neither PD-L1 nor TMB alone captures antigen quality, HLA presentation, clonality, or suppressive microenvironment (Yu 2019, PMID 30253973).

CheckMate 227 established durable nivolumab/ipilimumab benefit in metastatic NSCLC and catalyzed TMB debate, but TMB did not become a universally required clinical selector (Paz-Ares 2022, PMID 34648948). Assay breadth, germline filtering, cutoff, and tumor purity change the number.

KEAP1/NFE2L2 alterations associate with redox adaptation and poor outcome; a LUSC chemo-IO study linked NRF2 and immune microenvironment to clinical efficacy, but prospective treatment interaction remains unproven (Duan 2023, PMID 38052215).

Primary and acquired resistance

Resistance layer Examples Potential strategy
No effective priming Low neoantigen clonality, dendritic-cell failure Vaccination, innate agonists, radiation—investigational
Antigen-presentation loss HLA/B2M/IFN-pathway disruption Bypass PD-1 dependence; no standard
T-cell exclusion Myeloid/stromal barriers, absent CXCL9/10 Myeloid/chemokine targeting
Exhaustion beyond PD-1 CTLA-4, LAG3, TIGIT, TIM3, VISTA Combination trials; toxicity and prior failures matter
Oncogenic metabolic suppression NRF2/KEAP1, hypoxia, adenosine Metabolic/redox combinations
Acquired immune editing Loss of neoantigen clones or JAK/IFN response Serial tissue/ctDNA studies

The exhausted immune class and 9p/IFN-loss work offer coherent mechanisms for immune-cold or checkpoint-resistant states but require LUSC prospective validation (Yang 2022, PMID 35799269; Zhao 2025, PMID 39725169).

What failed after or alongside checkpoint therapy

S1400I randomized 252 eligible pretreated, IO-naïve LUSC patients to nivolumab/ipilimumab versus nivolumab. OS was 10 versus 11 months (HR 0.87, 95% CI 0.66–1.16); response 18% versus 17%; grade ≥3 treatment-related AE 39.5% versus 33.3% (Gettinger 2021, PMID 34264316).

S1400F treated 58 PD-(L)1-resistant LUSC patients with durvalumab/tremelimumab. Primary resistance yielded two responses (7%, 95% CI 0–17); acquired resistance yielded none. Median PFS was 2.0–2.1 months and grade ≥3 possibly related AEs occurred in 34% (Leighl 2021, PMID 34429332).

These trials refute indiscriminate CTLA-4 addition while leaving open biomarker-selected combinations.

Locally advanced and perioperative immunotherapy

After concurrent chemoradiation for unresectable stage III NSCLC, durvalumab improved survival in PACIFIC; five-year outcomes established a durable curative-intent standard across a mixed-histology population (Antonia 2017, PMID 28885881; Spigel 2022, PMID 35108059). Squamous-specific treatment interaction is not established.

Neoadjuvant and perioperative checkpoint therapy in resectable NSCLC also enrolls both histologies; details are in early-stage and perioperative therapy.

Checkpoint toxicity differs from chemotherapy because any organ can be inflamed and onset may be delayed. ASCO guidance generally continues therapy with close monitoring for grade 1 (except selected cardiac, neurologic, and hematologic toxicities), holds most grade 2, gives high-dose corticosteroids for grade 3, and permanently discontinues for most grade 4 toxicities; steroid taper commonly extends 4–6 weeks (Schneider 2021, PMID 34724392).

Organ system Examples LUSC-specific relevance
Lung Pneumonitis COPD, prior radiation, infection, and tumor obstruction complicate diagnosis
Endocrine Thyroiditis, hypophysitis, adrenal insufficiency, diabetes May require lifelong replacement rather than permanent IO cessation
GI/hepatic Colitis, hepatitis Distinguish from infection/drug toxicity
Cardiac Myocarditis, conduction disease Rare, potentially fatal; low threshold for workup
Neurologic Myasthenia, neuropathy, encephalitis Can overlap paraneoplastic syndromes
Skin Rash, pruritus, severe cutaneous reactions Common mild; rare life-threatening variants

Open questions

  • Which baseline signature identifies the 18.4% five-year KEYNOTE-407 survivors without conditioning on response (Novello 2023, PMID 36735893)?
  • Can exhausted/high-PD-L1 tumors be prospectively recognized and converted to effective immunity (Yang 2022, PMID 35799269)?
  • What is the optimal post-chemo-IO sequence after CTLA-4 rescue failure (Leighl 2021, PMID 34429332)?
  • Does ctDNA clearance add actionable early information beyond imaging, and should non-clearance trigger treatment change (Ren 2022, PMID 34923163)?
  • Can treatment duration be shortened in deep responders without losing the durable tail?

References

  1. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-35. PMID 26028407
  2. Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, et al. Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer. J Clin Oncol. 2021;39(7):723-733. PMID 33449799
  3. Reck M, Taylor F, Penrod JR, DeRosa M, Morrissey L, Dastani H, et al. Impact of Nivolumab versus Docetaxel on Health-Related Quality of Life and Symptoms in Patients with Advanced Squamous Non-Small Cell Lung Cancer: Results from the CheckMate 017 Study. J Thorac Oncol. 2018;13(2):194-204. PMID 29129758
  4. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2040-2051. PMID 30280635
  5. Novello S, Kowalski DM, Luft A, Gümüş M, Vicente D, Mazières J, et al. Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol. 2023;41(11):1999-2006. PMID 36735893
  6. Borghaei H, Langer CJ, Paz-Ares L, Rodríguez-Abreu D, Halmos B, Garassino MC, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer without tumor PD-L1 expression: A pooled analysis of 3 randomized controlled trials. Cancer. 2020;126(22):4867-4877. PMID 32914866
  7. Gadgeel SM, Rodríguez-Abreu D, Halmos B, Garassino MC, Kurata T, Cheng Y, et al. Pembrolizumab Plus Chemotherapy for Metastatic NSCLC With Programmed Cell Death Ligand 1 Tumor Proportion Score Less Than 1%: Pooled Analysis of Outcomes After Five Years of Follow-Up. J Thorac Oncol. 2024;19(8):1228-1241. PMID 38642841
  8. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823-1833. PMID 27718847
  9. Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020;383(14):1328-1339. PMID 32997907
  10. Kilickap S, Baramidze A, Sezer A, Özgüroğlu M, Gumus M, Bondarenko I, et al. Cemiplimab Monotherapy for First-Line Treatment of Patients with Advanced NSCLC With PD-L1 Expression of 50% or Higher: Five-Year Outcomes of EMPOWER-Lung 1. J Thorac Oncol. 2025;20(7):941-954. PMID 40118215
  11. Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodríguez-Abreu D, Hussein M, et al. Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. J Thorac Oncol. 2020;15(8):1351-1360. PMID 32302702
  12. Reck M, Ciuleanu TE, Schenker M, Bordenave S, Cobo M, Juan-Vidal O, et al. Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial. Eur J Cancer. 2024;211:114296. PMID 39270380
  13. Carbone DP, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, et al. Nivolumab plus ipilimumab with chemotherapy as first-line treatment of patients with metastatic non-small-cell lung cancer: final, 6-year outcomes from CheckMate 9LA. ESMO Open. 2025;10(6):105123. PMID 40446626
  14. Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022;28(11):2374-2380. PMID 36008722
  15. Ren S, Chen J, Xu X, Jiang T, Cheng Y, Chen G, et al. Camrelizumab Plus Carboplatin and Paclitaxel as First-Line Treatment for Advanced Squamous NSCLC (CameL-Sq): A Phase 3 Trial. J Thorac Oncol. 2022;17(4):544-557. PMID 34923163
  16. Yu H, Chen Z, Ballman KV, Watson MA, Govindan R, Lanc I, et al. Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma. J Thorac Oncol. 2019;14(1):25-36. PMID 30253973
  17. Paz-Ares LG, Ramalingam SS, Ciuleanu TE, Lee JS, Urban L, Caro RB, et al. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. J Thorac Oncol. 2022;17(2):289-308. PMID 34648948
  18. Duan J, Zhang Y, Chen R, Liang L, Huo Y, Lu S, et al. Tumor-immune microenvironment and NRF2 associate with clinical efficacy of PD-1 blockade combined with chemotherapy in lung squamous cell carcinoma. Cell Rep Med. 2023;4(12):101302. PMID 38052215
  19. Yang M, Lin C, Wang Y, Chen K, Zhang H, Li W. Identification of a cytokine-dominated immunosuppressive class in squamous cell lung carcinoma with implications for immunotherapy resistance. Genome Med. 2022;14(1):72. PMID 35799269
  20. Zhao X, Liu B, William WN, Tsanov KM, Ho YJ, Barriga FM, et al. Interferon Epsilon Loss Is Elusive 9p21 Link to Immune-Cold Tumors, Resistant to Immune Checkpoint Therapy, and Endogenous CXCL9/10 Induction. J Thorac Oncol. 2025;20(9):1177-1236. PMID 39725169
  21. Gettinger SN, Redman MW, Bazhenova L, Hirsch FR, Mack PC, Schwartz LH, et al. Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021;7(9):1368-1377. PMID 34264316
  22. Leighl NB, Redman MW, Rizvi N, Hirsch FR, Mack PC, Schwartz LH, et al. Phase II study of durvalumab plus tremelimumab as therapy for patients with previously treated anti-PD-1/PD-L1 resistant stage IV squamous cell lung cancer (Lung-MAP substudy S1400F, NCT03373760). J Immunother Cancer. 2021;9(8). PMID 34429332
  23. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-1929. PMID 28885881
  24. Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2022;40(12):1301-1311. PMID 35108059
  25. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol. 2021;39(36):4073-4126. PMID 34724392