Favorable clinical outcomes of checkpoint inhibitor-based combinations after progression with immunotherapy in advanced non-small cell lung cancer

Abstract

Aim: Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment paradigm in patients with non-small-cell lung cancer (NSCLC). However, progression patterns with immunotherapy are currently unclear and therapeutic options beyond resistance remain challenging.

Methods: We reviewed advanced NSCLC patients between January 2016 and December 2019 who were treated with anti-PD-1/PD-L1 inhibitors in our center and identified those who developed disease progression. Later-line treatment strategies were collected and objective response rate, progression-free survival (PFS), and overall survival (OS) were assessed.

Results: Of the 118 patients, 46 (39.0%) showed oligoprogression and 72 (61.0%) showed systemic progression. No difference in progression patterns was observed between monotherapy and combination therapy. Systemic progression was strongly associated with never-smokers (51.4% vs. 21.7%, P = 0.001) and ECOG PS = 2 (13.9% vs. 2.2%, P = 0.048) at baseline. The distribution of progression sites was roughly similar between oligoprogression and systemic progression, and the most commonly affected anatomic site was lung (66.9%), followed by bone (12.7%) and lymph nodes (11.0%). For patients beyond first disease progression, checkpoint inhibitor-based combinations could lead to a significantly longer PFS2 compared with ICIs monotherapy (9.63 months vs. 4.23 months, P = 0.004, HR = 0.394, 95%CI: 0.174-0.893) and other therapy (9.63 months vs. 4.07 months, P = 0.046, HR = 0.565, 95%CI: 0.326-0.980). Median OS of the ICIs combination group was not reached but was significantly longer than other therapy group (NR vs. 14.37 months, P = 0.010, HR = 0.332, 95%CI: 0.167-0.661).

Conclusion: Systemic progression occurs more frequently among NSCLC patients receiving ICIs. Checkpoint inhibitor-based combinations show favorable outcomes as subsequent treatment strategies after the failure of previous ICIs treatment.

Keywords

Immunotherapy / non-small cell lung cancer (NSCLC) / patterns of progression / treatment beyond progression (TBP)

References

[1] Arbour KC.Systemic therapy for locally advanced and metastatic non-small cell lung cancer: a review.JAMA2019;322:764-74

[2] Doroshow DB,Hastings K.Immunotherapy in non-small cell lung cancer: facts and hopes.Clin Cancer Res2019;25:4592-02 PMCID:PMC6679805

[3] Garon EB,Rizvi NA.Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study.J Clin Oncol2019;37:2518-27 PMCID:PMC6768611

[4] Hellman S.Oligometastases.J Clin Oncol1995;13:8-10

[5] Lehrer EJ,Wang M.Safety and survival rates associated with ablative stereotactic radiotherapy for patients with oligometastatic cancer: a systematic review and meta-analysis.JAMA Oncol2021;7:92-106 PMCID:PMC7689573

[6] Yu HA,Huang J.Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors.J Thorac Oncol2013;8:346-51 PMCID:PMC3673295

[7] Li XY,Zhang CC.Analysis of progression patterns and failure sites of patients with metastatic lung adenocarcinoma with EGFR mutations receiving first-line treatment of tyrosine kinase inhibitors.Clin Lung Cancer2020;21:534-44

[8] Xu Q,Meng S.First-line continual EGFR-TKI plus local ablative therapy demonstrated survival benefit in EGFR-mutant NSCLC patients with oligoprogressive disease.J Cancer2019;10:522-9 PMCID:PMC6360299

[9] Schmid S,Aeppli S.Patterns of progression on osimertinib in EGFR T790M positive NSCLC: A Swiss cohort study.Lung Cancer2019;130:149-55

[10] Billan S,Gil Z.Treatment after progression in the era of immunotherapy.Lancet Oncol2020;21:e463-76

[11] Brahmer J,Baas P.Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med2015;373:123-35 PMCID:PMC4681400

[12] Fehrenbacher L,Ballinger M.Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.Lancet2016;387:1837-46

[13] Rittmeyer A,Waterkamp D,Ciardiello F.Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.Lancet2017;389:255-65 PMCID:PMC6886121

[14] Gandara DR,Mazieres J.Atezolizumab treatment beyond progression in advanced NSCLC: results from the randomized, phase III OAK study.J Thorac Oncol2018;13:1906-18

[15] Ricciuti B,Bassanelli M.Safety and efficacy of nivolumab in patients with advanced non-small-cell lung cancer treated beyond progression.Clin Lung Cancer2019;20:178-85.e2

[16] Reinhorn D,Icht O.Treatment beyond progression with immune checkpoint inhibitors in non-small-cell lung cancer.Immunotherapy2020;12:235-43

[17] Stinchcombe TE,Gossai A,Torres AZ.Real-world outcomes for advanced non-small cell lung cancer patients treated with a PD-L1 inhibitor beyond progression.Clin Lung Cancer2020;21:389-94.e3

[18] Enomoto T,Matsumoto K.Nivolumab treatment beyond progressive disease in advanced non-small cell lung cancer.Clin Transl Oncol2021;23:582-90

[19] Metro G,Signorelli D.Outcomes from salvage chemotherapy or pembrolizumab beyond progression with or without local ablative therapies for advanced non-small cell lung cancers with PD-L1 ≥ 50% who progress on first-line immunotherapy: real-world data from a European cohort.J Thorac Dis2019;11:4972-81 PMCID:PMC6988053

[20] Rheinheimer S,Mayer P.Oligoprogressive non-small-cell lung cancer under treatment with PD-(L)1 inhibitors.Cancers (Basel)2020;12:1046-58 PMCID:PMC7226015

[21] Kagawa Y,Uemura T.Efficacy of local therapy for oligoprogressive disease after programmed cell death 1 blockade in advanced non-small cell lung cancer.Cancer Sci2020;111:4442-52 PMCID:PMC7734009

[22] Li JJN,Sung M.Tobacco exposure and immunotherapy response in PD-L1 positive lung cancer patients.Lung Cancer2020;150:159-63

[23] Singal G,Agarwala V.Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a Clinicogenomic Database.JAMA2019;321:1391-9 PMCID:PMC6459115

[24] Lobefaro R,Di Liello R.Immunotherapy in advanced non-small cell lung cancer patients with poor performance status: The role of clinical-pathological variables and inflammatory biomarkers.Lung Cancer2020;152:165-73

[25] George S,Hammers HJ.Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial.JAMA Oncol2016;2:1179-86 PMCID:PMC5568541

[26] Escudier B,Sharma P.Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025.Eur Urol2017;72:368-76

[27] Long GV,Larkin J.Nivolumab for patients with advanced melanoma treated beyond progression: analysis of 2 phase 3 clinical trials.JAMA Oncol2017;3:1511-9 PMCID:PMC5710191

[28] Beaver JA,Mulkey F.Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis.Lancet Oncol2018;19:229-39 PMCID:PMC5806609

[29] Emens LA.The interplay of immunotherapy and chemotherapy: harnessing potential synergies.Cancer Immunol Res2015;3:436-43 PMCID:PMC5012642

[30] Leonetti A,Mazzaschi G.Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer.Drug Resist Updat2019;46:100644

[31] Fukumura D,Amoozgar Z,Jain RK.Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.Nat Rev Clin Oncol2018;15:325-40 PMCID:PMC5921900

[32] Huang Y,Chan CK.Improving immune-vascular crosstalk for cancer immunotherapy.Nat Rev Immunol2018;18:195-203 PMCID:PMC5922422

[33] Ngwa W,Schoenfeld JD.Using immunotherapy to boost the abscopal effect.Nat Rev Cancer2018;18:313-22 PMCID:PMC5912991

[34] Sharabi AB,DeWeese TL.Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy.Lancet Oncol2015;16:e498-509

[35] Mariniello A,Scagliotti GV.Double immune checkpoint blockade in advanced NSCLC.Crit Rev Oncol Hematol2020;152:102980

[36] Mildner F,Amann A.Systematic review: Soluble immunological biomarkers in advanced non-small-cell lung cancer (NSCLC).Crit Rev Oncol Hematol2020;153:102948