According to a study published online in the March 16, 2021 edition of Oncotarget there is, unlike lung adenocarcinoma patients, no FDA-approved targeted therapy regimens available to benefit lung squamous cell carcinoma patients. The authors of the article concluded that this was ‘in spite of distinct genetic alterations identified in the tumor type.’ [1]

As part of their study, the researchers performed survival analyses of lung squamous cell carcinoma patients harboring therapeutically relevant alterations identified by whole-exome sequencing and mass spectrometry-based validation across 430 lung squamous tumors.

They reported a mean of 11.6 mutations/Mb with a characteristic smoking signature along with mutations in TP53 (65%), CDKN2A (20%), NFE2L2 (20%)FAT1 (15%)KMT2C (15%), LRP1B (15%), FGFR1 (14%), PTEN (10%) and PREX2 (5%) among lung squamous cell carcinoma patients of Indian descent.

Overall, the data suggests 13.5% of lung squamous patients harboring druggable mutations have lower median overall survival, and 19% of patients with a mutation in at least one gene, known to be associated with cancer, result in significantly shorter median overall survival compared to those without mutations.

The study is the first comprehensive landscape of genetic alterations underlying Indian lung squamous cell carcinoma patients and identifies EGFR, PIK3CA, KRAS, and FGFR1 as potentially important therapeutic and prognostic targets.

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“Lung cancer is the leading cause of cancer-related deaths across the globe with more than 1.7 million deaths annually.” Amit Dutt, MD, Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra 410210, India, said.

Significant tobacco use
Non-small cell lung cancer, a more common type of lung cancer, accounts for 85% of all lung cancers comprising two major histological subtypes, adenocarcinoma, and squamous cell carcinoma.

The adenocarcinoma of the lung arises mostly in patients with no previous significant tobacco exposure, while the squamous subtype is found almost exclusively in former or current smokers with a relatively higher overall mutational load.

However, there is no approved targeted therapy regimen available for lung squamous patients in spite of distinct genetic alterations identified in the tumor type. Furthermore, most of the reported studies describe Caucasian, Chinese, Korean, and Japanese populations, with sparse information on the molecular profile of lung squamous patients of Indian origin that accounts for about 30% of Indian lung cancer disease.

In their study, the authors sought to describe the first genetic landscape of alterations underlying 430 Indian lung squamous genomes and uncover the prevalence of known targetable somatic alterations using next-generation sequencing followed by validation using mass spectrometry.

“We’ve presented a striking variation of genetic heterogeneity among lung squamous cell carcinoma patients of Indian descent. The findings from this study extend the scope of the ongoing umbrella clinical trials such as the Lung-MAP master protocol that aims to evaluate multiple targeted therapeutic strategies in lung squamous cell carcinoma patients and the AACR Project GENIE database collaborative project,” noted Kumar Prabhash, MD, at the Department of Medical Oncology, Tata Memorial Centre, Ernest Borges Marg, Parel, Mumbai, Maharashtra 400012, India explained.

“A systematic exploration of these target genes in lung squamous cell carcinoma patients and variability across ethnicity could further extend our insights into the etiology of lung squamous cancer,” Dutt concluded.

Advanced disease
Although the authors of the study note that there is no approved targeted therapy regimen available for lung squamous patients in spite of distinct genetic alterations identified in the tumor type, options for the treatment of squamous cell lung carcinoma with mutations of ErbB, (especially HER2), have expanded in recent years with the introduction of the immune checkpoint inhibitors into routine clinical practice in both the first- and second-line settings.

However, treatment options in this setting are still limited. As a result, pembrolizumab, given either alone or in combination with platinum-based chemotherapy, is now a standard first-line treatment for squamous cell lung cancer. [2]

Unfortunately, only a few options exist once patients have progressed on immune checkpoint inhibitors and chemotherapy. In this setting, the irreversible ErbB family blocker, afatinib (Gilotrif; Boehringer Ingelheim Pharmaceuticals), has a potential role as second or subsequent therapy for some patients.

‘The Phase III LUX-Lung 8 study demonstrated that afatinib significantly prolonged progression-free and overall survival compared with erlotinib in patients with squamous cell lung carcinoma.

Researchers noted that retrospective, ad-hoc biomarker analyses of a subset of patients from LUX-Lung 8 suggested that patients with ErbB family mutations derived particular benefits from afatinib, especially those with ErbB2 (HER2) mutations.

The approval of afatinib for use in patients who have progressed on platinum-based chemotherapy was based on results from the open-label, Phase III LUX-Lung 8 study, which compared the second-line use of afatinib (n=398) with erlotinib (n=397) in patients with advanced squamous cell lung cancer. Median PFS was longer with afatinib compared with erlotinib (2.4 months [95% CI=1.9–2.9] versus 1.9 months [95% CI=1.9–2.2]; HR=0.82 [95% CI=0.68–1.00], P=0.0427), as was OS (median 7.9 months [95% CI=7.2–8.7] versus 6.8 months [95% CI=5.9–7.8]; HR=0.81 [95% CI=0.69–0.95], P=0.0077) Although the proportion of patients with an objective response did not differ significantly between the treatment groups (6% versus 3%, P=0.055), the disease control rate was significantly higher in the afatinib group (51% versus 40%, P=0.002).

Afatinib a second-generation, irreversible ErbB family blocker that inhibits signaling from all ErbB hetero- and homodimers, conferring a wider inhibitory profile than first-generation, reversible EGFR-specific agents such as erlotinib and gefitinib, has a manageable and predictable safety profile, and adverse events can be managed with the use of a tolerability-guided dose modification protocol.

Clinical trials
LUX-Lung 8: A Phase III Trial of Afatinib (BIBW 2992) Versus Erlotinib for the Treatment of Squamous Cell Lung Cancer After at Least One Prior Platinum-based Chemotherapy – NCT01523587

Highlights of prescribing information
Afatinib (Gilotrif®; Boehringer Ingelheim Pharmaceuticals) [Prescribing Information]

[1] Joshi, A, Mishra, R, Desai, S, Chandrani, P, Kore, H, Sunder, R, Hait, S, Iyer, P, Trivedi, V, Choughule, A, Noronha, V, Joshi, A, Patil, V, Menon, N, Kumar, R, Prabhash, K, & Dutt, A. Molecular characterization of lung squamous cell carcinoma tumors reveals therapeutically relevant alterations. Oncotarget 2021 Mar 16;12(6):578-588
[2] Santos ES, Hart L. Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib. Onco Targets Ther. 2020;13:9305-9321

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