Predictive molecular pathology in lung cancer: the oncologist point of view

Lung cancer certainly represents a successful example of the predictive molecular pathology paradigm application in cancer care, since it has become clear that the routine testing for molecular alterations and the progressive introduction of targeted therapies allowed to significantly reduce patients’ mortality (1). Following the initial identification of epidermal growth factor receptor (EGFR) activating mutations as molecular predictor of EGFR tyrosine kinase inhibitors (TKIs) activity (2) in non-small cell lung cancer (NSCLC) patients, the number of molecular biomarkers has rapidly increased over the last few years, leading to a radical shift from histological to molecular subtype of lung cancer. Tumor molecular profiling is now considered a crucial step of the diagnostic and therapeutic management of metastatic non-squamous NSCLC, allowing to personalize therapeutic strategies and ultimately improve patients’ survival.

Novel, potent, and highly selective TKIs are progressively entering the treatment algorithm of lung cancer patients harboring oncogenic drivers, including both clinical approved biomarkers, such as EGFR (12–15%), ALK (3–8%), ROS1 (1–2%), BRAF (2–4%), and NTRK (0.5–1%), and emerging ones, like RET (1–2%), MET exon14 skipping (2–3%), KRASp.G12C (10–12%), HER2 (2–3%), with targeted agents available either in clinical trials or in the real-world scenario. The advent of the third-generation EGFR-TKI, osimertinib, established a new survival plateau approaching 40 months in metastatic patients harboring EGFR-common alterations (Del19 and L858R) included within the phase III randomized FLAURA trial (3), while we have recently celebrated the regulatory approval of novel agents targeting the EGFR exon20 insertions, amivantamab and mobocertinib, offering new targeted opportunities to this hard to treat subgroup of EGFR-positive patients. A series of new generation TKIs, characterized by high intracranial activity and optimal tolerability, is now available for the clinical treatment of both ALK- (alectinib, brigatinib, ceritinib, ensartinib, lorlatinib) and ROS1-rearranged (crizotinib, entrectinib) NSCLC patients, reaching unprecedented survival outcomes and quality of life (4). Whether dual BRAF-MEK targeted inhibition by dabrafenib and trametinib combination certainly represents the most effective therapy for BRAF-V600E mutant NSCLC (5), however there are some concerns regarding the best upfront treatment for both non-V600E and non-V600 BRAF-mutant disease, considering the very low certainty of evidence coming from available studies and the lack of randomized comparison versus chemo-immunotherapeutic regimens. The promising results of phase I/II ARROW and LIBRETTO studies (6,7) have recently prompted the clinical approval of novel selective RET inhibitors, Pralsetinib and Selpercatinib, for the clinical treatment of pre-treated advanced NSCLC harboring RET-fusions, while the potential role of these agents in first-line is currently being investigated. Similarly, the phase II VISION and GEOMETRY studies showed encouraging antitumor activity with two different small molecules, tepotinib and capmatinib, selectively targeting MET exon 14 skipping alterations (8,9). A third selective inhibitor, savolitinib, has shown its activity in patients with sarcomatoid histology harboring the same molecular alteration (10). The recent resolution of the KRASp.G12C binding pocket has been crucial to developing a new class of mutant-directed inhibitors, able to covalently bind and trap KRASp.G12C in its inactive state. These pre-clinical proof of principle have broken down the dogma that mutant KRAS was undruggable, leading to the design of early phase clinical studies testing selective KRASp.G12C inhibitors in patients with previously treated advanced NSCLC harboring p.G12C mutation subtype. Preliminary activity data emerging from both CodeBreak 101 and KRYSTAL-1 studies, suggested that both sotorasib and adagrasib are potential effective targeted options to be offered to about 12% of advanced NSCLC patients harboring KRASp.G12C mutation (11,12), gathering further investigation in larger randomized confirmatory studies. Preliminary results from the phase II DESTINY-Lung01 study, demonstrated great and durable tumor responses with the new anti-HER2 antibody-drug conjugate (ADC), trastuzumab deruxtecan, in heavily pre-treated, advanced NSCLC patients harboring HER2-mutations, definitively interrupting the negative trend of HER2 inhibition in lung cancer (13). Finally, larotrectinib and entrectinib are two selective TRK-inhibitors recently approved by regulatory authorities as tissue agnostic therapeutic options for patients with metastatic solid tumors harboring NTRK-rearrangements, regardless of tumor histotypes and/or lines of therapy (14,15).

The identification of an increasing number of “rare” targetable molecular alterations favoured the accelerated approval of novel molecules, based on biomarker-driven, early phase clinical studies results. Innovative umbrella design, including the LUNG-MAP Master Protocol (16) and the Lung-Matrix Trial (17) explored novel clinical research infrastructure, allowing the simultaneous testing of different genotype-based targeted therapies in molecularly selected cohorts. International cancer scientific societies have recently endorsed next generation sequencing (NGS)-based molecular profiling as a key component of NSCLC patients’ standard management and care (18), definitively ensuring adequate detection of some elusive targets, like EGFR exon 20 insertion variants and NTRK rearrangements. However national molecular testing guidelines are still too heterogeneous across different European countries, and several additional logistic, cultural, and socioeconomic barriers limited patients’ access to NGS-based molecular profiling and matched targeted treatments (19).

Tissue still represents the main issue in the era of predictive molecular pathology, while the liquid biopsy is emerging as a non-invasive reliable alternative approach with possible applications in different scenarios. A series of diagnostic accuracy clinical studies have definitively demonstrated a high concordance between tissue and ctDNA NGS-based molecular profiling (20,21), leading to the recent approval of the first ctDNA NGS diagnostic assay for the molecular profiling of advanced NSCLC patients in the United States. The ctDNA NGS analysis has shown to accurately detect molecular mechanisms of acquired resistance under TKI therapy, allowing longitudinal tracking of somatic alterations during the treatment course (22). Since predictive molecular pathology is now considered as a standard approach in the clinical management of advanced disease, it’s progressively moving also to the early stages setting. After several years of clinical research, the randomized ADAURA trial (23) showed that the adjuvant administration of osimertinib, produced a dramatic increase of disease-free recurrence rate in surgically resected NSCLC patients harboring common EGFR-mutations, suggesting that the application of predictive molecular pathology paradigm in the early stage disease is feasible and supporting the routine use of molecular profile and targeted treatments in oncogene addicted, surgically resected patients. Recent findings revealed that the post-surgical assessment and monitoring of minimal residual disease (MRD) could provide reliable information on patients’ prognosis and risk of disease relapse (24), offering the opportunity to identify high-risk subgroups who are best candidates to adjuvant therapies. The prospective validation of MRD as prognostic biomarker within ongoing phase II-III clinical studies, will likely allow to further personalize treatment of early stage disease, overcoming traditional drug-development and regulatory procedures.

The application of predictive molecular pathology paradigm into the real-word clinical scenario is inevitably associated to the emergence of unavoidable challenges, including the safe and equal implementation of NGS-based molecular testing, the increased access of lung cancer patients to biomarker driven-clinical trials, the accurate preservation of the health systems’ financial sustainability worldwide, requiring joined efforts at the global level.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Umberto Malapelle and Giancarlo Troncone) for the series “Predictive Molecular Pathology in Lung Cancer” published in Journal of Xiangya Medicine. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jxym.amegroups.com/article/view/10.21037/jxym-21-53/coif). The series “Predictive Molecular Pathology in Lung Cancer” was commissioned by the editorial office without any funding or sponsorship. FP declares consultant’s fee from: AstraZeneca, Janssen, Amgen, Thermo fisher Scientific; Paolo Bironzo received honoraria as speaker’s bureau by Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Merck Sharp and Dohme; he declares expenses by Amgen and Daiichi Sankyo; he received institutional research funding from Roche and Pfizer. SN declares speaker bureau/advisor’s fee from: Eli Lilly, Merck Sharp and Dohme, Roche, Bristol-Myers Squibb, Takeda, Pfizer, Astra Zeneca and Boehringer Ingelheim, and support for attending meetings and/or travel from Amgen and Daiichi Sankyo. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Howlader N, Forjaz G, Mooradian MJ, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med 2020;383:640-9. [Crossref] [PubMed]
2. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39. [Crossref] [PubMed]
3. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020;382:41-50. [Crossref] [PubMed]
4. Remon J, Pignataro D, Novello S, et al. Current treatment and future challenges in ROS1- and ALK-rearranged advanced non-small cell lung cancer. Cancer Treat Rev 2021;95:102178. [Crossref] [PubMed]
5. Planchard D, Besse B, Groen HJM, et al. Updated overall survival (OS) and genomic analysis from a single-arm phase II study of dabrafenib (D) + trametinib (T) in patients (pts) with BRAF V600E mutant (Mut) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2020;38:9593. [Crossref]
6. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2020;383:813-24. [Crossref] [PubMed]
7. Gainor JF, Lee DH, Curigliano G, et al. Clinical activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients (pts) with advanced RET-fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol 2019;37:9008. [Crossref]
8. Wolf J, Seto T, Han JY, et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med 2020;383:944-57. [Crossref] [PubMed]
9. Paik PK, Felip E, Veillon R, et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med 2020;383:931-43. [Crossref] [PubMed]
10. Lu S, Fang J, Li X, et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study. Lancet Respir Med 2021;9:1154-64. [Crossref] [PubMed]
11. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med 2020;383:1207-17. [Crossref] [PubMed]
12. Jänne PA, Rybkin II, Spira AI, et al. KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/ Metastatic Non–Small-Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation. Eur J Cancer 2020;138:S1-2. [Crossref]
13. Li BT, Smit EF, Goto Y, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med 2022;386:241-51. [Crossref] [PubMed]
14. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271-82. [Crossref] [PubMed]
15. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 2020;21:531-40. [Crossref] [PubMed]
16. Redman MW, Papadimitrakopoulou VA, Minichiello K, et al. Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol. Lancet Oncol 2020;21:1589-601. [Crossref] [PubMed]
17. Middleton G, Fletcher P, Popat S, et al. The National Lung Matrix Trial of personalized therapy in lung cancer. Nature 2020;583:807-12. [Crossref] [PubMed]
18. Mosele F, Remon J, Mateo J, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2020;31:1491-505. [Crossref] [PubMed]
19. Kerr KM, Bibeau F, Thunnissen E, et al. The evolving landscape of biomarker testing for non-small cell lung cancer in Europe. Lung Cancer 2021;154:161-75. [Crossref] [PubMed]
20. Leighl NB, Page RD, Raymond VM, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clin Cancer Res 2019;25:4691-700. [Crossref] [PubMed]
21. Zugazagoitia J, Ramos I, Trigo JM, et al. Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping. Ann Oncol 2019;30:290-6. [Crossref] [PubMed]
22. Rolfo C, Mack P, Scagliotti GV, et al. Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer. J Thorac Oncol 2021;16:1647-62. [Crossref] [PubMed]
23. Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med 2020;383:1711-23. [Crossref] [PubMed]
24. Abbosh C, Frankell A, Garnett A et al. Abstract CT023: Phylogenetic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx study. Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA.