Promise and Need for More Progress in Treatment of Squamous Cell NSCLC

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A greater understanding of the mutational landscape in non–small cell lung cancer (NSCLC) has identified key oncogenes, such as EGFR, ALK, ROS, RET, and BRAF, among others. These discoveries, coupled with the availability of specific targeted small-molecule inhibitors, have transformed the management of patients with nonsquamous NSCLC with actionable driver mutations. In turn, this has led to molecular profiling of patients’ tumors as standard of care to guide personalized medicine approaches.

Squamous cell lung cancer is a unique subset of NSCLC with an aggressive phenotype. Unlike adenocarcinoma, where genomic profiling is part of standard of care, there are limited data on the activity and efficacy of targeted agents for this subset of patients.1 At the same time, therapeutic progress in squamous cell lung cancer has been relatively slow, with stagnation of survival numbers, in the 9- to 11-month range, and no substantial improvement until recently. In addition, squamous cell histology also offers distinct therapeutic challenges by virtue of presentation in older patients, its pattern of metastasis, and association with comorbidities that can compromise treatment delivery and exacerbate toxicity.

Charu Aggarwal, MD, MPH

Charu Aggarwal, MD, MPH

A New Era of Antineoplastic Therapy

The use of immune checkpoint blockade of CTLA-4, PD-1, and PD-L1 has ushered in a new era of antineoplastic therapy and has transformed the landscape of management of patients with advanced NSCLC. The initial breakthrough came with the KEYNOTE-024 phase III trial for patients with untreated stage IV NSCLC with a PD-L1 level greater than 50%. Pembrolizumab was associated with a clear and strong signal of activity vs standard-of-care chemotherapy, including a response rate of about 45%, improvement in progression-free survival, and a clear survival benefit with a hazard ratio of 0.6.2 Based on this trial, pembrolizumab is currently the standard of care for patients with advanced metastatic chemotherapy-naive NSCLC, with a PD-L1 tumor proportion score greater than 50%. Atezolizumab and cemiplimab are also now approved in this setting, for patients with high PD-L1 expression.3,4

And, we now have data demonstrating the superiority of combination chemotherapy and immunotherapy for patients with squamous NSCLC. The phase III KEYNOTE-407 trial of combination platinum/taxane with or without pembrolizumab in patients with untreated metastatic squamous NSCLC showed an improved overall response rate with combination chemoimmunotherapy (58.4% vs 35.0% P = .0004) and an improvement in overall survival.5 Combination immunotherapy with nivolumab and ipilimumab, either alone or in combination with chemotherapy as a quadruplet regimen, has also been approved in the setting of newly diagnosed treatment-naive metastatic NSCLC.6,7 Although single-agent immunotherapy is the current standard of care for squamous NSCLC with a PD-L1 tumor proportion score greater than 50%, chemoimmunotherapy has now been established as the standard of care in patients with a PD-L1 tumor proportion score less than 50%.

Adding a PARP Inhibitor to the Mix

Even though we have witnessed significant improvements in outcomes, many patients do not respond to immunotherapy. PD-L1 tumor proportion score is currently used to select patients for immune therapy; however, it is an imperfect biomarker, as it does not accurately predict which patients are destined to respond. There is an urgent need for personalized medicine approaches to identify and validate biomarkers that will help us identify novel therapies and select appropriate patients for therapy.

In a phase III trial reported by Ramalingam et al8 and summarized in the December 25, 2021, issue of The ASCO Post, the addition of the PARP inhibitor veliparib to platinum-based chemotherapy in previously untreated advanced squamous NSCLC did not improve overall survival in the subgroup of patients who were current smokers (primary analysis). However, a trend toward improvement was observed in the intention-to-treat population. A subgroup of patients had data available from biomarker analysis of tumor samples using the 52-gene expression histology classifier (LP52) to identify tumors with greater nonadenocarcinoma vs adenocarcinoma molecular characteristics (LP52-positive tumors). An improvement in overall survival with veliparib was observed among patients with LP52-positive disease, with an approximately 34% decrease in the risk of death compared with the control arm.

There are emerging data that PARP inhibitors may augment the activity of PD-L1 inhibitors and enhance the antitumor immunity through activation of the STING innate pathway. Based on the results of this study, further investigation of the role of PARP inhibitors in combination with chemoimmunotherapy is warranted. 

Dr. Aggarwal is the Leslye M. Heisler Associate Professor for Lung Cancer Excellence at the Perelman School of Medicine, University of Pennsylvania, Philadelphia.

DISCLOSURE: Dr. Aggarwal has served as a consultant or advisor to AstraZeneca, Blueprint Genetics, Celgene, Daiichi Sankyo, Genentech, Lilly, Merck, and Shionogi; has an immediate family member who has participated in a speakers bureau for AstraZeneca and Roche/Genentech; and has received institutional research funding from AstraZeneca/MedImmune, Genentech/Roche, Incyte, MacroGenics, and Merck Sharp & Dohme.


1. Choi M, Kadara H, Zhang J, et al: Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function. Ann Oncol 28:83-89, 2017.

2. Reck M, Rodríguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375:1823-1833, 2016.

3. Herbst RS, Giaccone G, de Marinis F, et al: Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N Engl J Med 383:1328-1393, 2020.

4. Sezer A, Kilickap S, Gümüş M, et al: Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: A multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 397:592-604, 2021.

5. Paz-Ares L, Luft A, Vicente D, et al: Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379:2040-2051, 2018.

6. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al: Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 381:2020-2031, 2019.

7. Paz-Ares L, Ciuleanu TE, Cobo M, et al: First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): An international, randomised, open-label, phase 3 trial. Lancet Oncol 22:198-211, 2021.

8. Ramalingam SS, Novello S, Guclu SZ, et al: Veliparib in combination with platinum-based chemotherapy for first-line treatment of advanced squamous cell lung cancer: A randomized, multicenter phase III study. J Clin Oncol 39:3633-3644, 2021.


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Addition of First-Line Veliparib to Chemotherapy in Advanced Squamous Cell NSCLC: No Survival Benefit in Current Smokers, but Potential Benefit Among Biomarker-Selected Patients

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In a phase III trial reported in the Journal of Clinical Oncology, Suresh S. Ramalingam, MD, of Winship Cancer Institute, Emory University School of Medicine, and colleagues found that the addition of the PARP inhibitor veliparib to platinum-based chemotherapy did not...