Treatment of metastatic lung cancer beyond 2020

Actionable mutations and immunotherapy

James Fleck: Anticancerweb 19(07), 2020

Worldwide epidemiological data point to lung cancer as the main malignant disease, both in incidence and mortality. According to IARC, almost 2.1 million cases are diagnosed annually, unfortunately showing a high CMR. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. NSCLC predominant morphological group, classified as non-squamous cell carcinoma (adenocarcinoma and large cell carcinoma) corresponds roughly to 70% of the cases and is followed by squamous cell carcinoma (30%). The last few years have revealed important advances in first-line treatment of metastatic NSCLC expressing actionable mutations. Patients with metastatic NSCLC, whose tumors expressed EGFR exon 19 deletions or exon 21 L858R mutation have been treated with a third generation TKI (osimertinib), achieving a median overall survival of 38.6 months, including cases with CNS metastases. Patients with metastatic NSCLC, harboring anaplastic lymphoma kinase gene rearrangement (ALK-positive), initially treated with crizotinib, achieved a median overall survival very close to 7 years, including persistent objective responses in CNS metastases. Metastatic NSCLC harboring ROS1 rearrangements are highly sensitive to entrectinib, a tropomyosin kinase receptor inhibitor. Crizotinib has also been used to treat ROS1-positive patients, due to observed homology of ALK and ROS tyrosine kinase domains. ROS1-positive NSCLC patients have a high incidence of brain metastases at presentation (36%), making entrectinib a better choice considering its effective CNS penetration. An integrated analysis of phase I and II ongoing studies have shown encouraging results. Entrectinib was associated to a 77% durable response rate (MRD = 24.5 months). MET and RET have also been described as potential targeted therapies. MET is a tyrosine kinase receptor for hepatocyte growth factor and  RET is the rearranged during transfection gene. Preliminary reports with MET inhibitors have been associated with response durations ranging from 9 to 11 months. Selpercatinib, a RET inhibitor, has shown a 64% durable RR (MRD = 18 months) in metastatic NSCLC, previously treated with platinum chemotherapy. Unfortunately, known actionable mutations are observed only in a small group of western patients. In USA, roughly 15% of NSCLC  patients are EGFR mutation-positive and only 5% express ALK-rearrangement. The percentage of NSCLC presenting ROS1 rearrangements, MET abnormalities and RET-fusion are around 2%, 2% and 6%, respectively. Currently, only 30% of metastatic NSCLC patients are potential candidates for targeted therapy. 

What happens to 70% of metastatic NSCLC who are not candidates for targeted therapy?

Fortunately, the concept of immunological checkpoint emerged. Since wild phenotypes of metastatic NSCLC are immunogenic, they could, hopefully, be sensitive to immunotherapy. Malignant tumors show a state of chronic antigen presentation. Twenty-years ago, the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) was identified as a negative regulator of the immune system, acting as a physiologic break on CD8+ T cell activation. CTLA-4 is upregulated under the influence of tumor cells. Consequently, the development of an anti-CTLA-4 monoclonal antibody (MoAb) was considered an interesting rationale to restore host immunocompetence.  Another mechanism, described later, is the protein cell-death 1 (PD1), a transmembrane protein expressed on T-cells. Curiously, many tumor cells have an upregulated expression of PD1-ligand (PD-L1). The interaction PD1 + PD-L1 promotes peripheral T effector cell exhaustion and inhibition of tumor cell apoptosis. Monoclonal antibodies against PD1 or PD-L1 emerged as effective options on cancer treatment.  The combination of nivolumab (MoAb anti-PD1) + ipilimumab (MoAb anti- CTLA-4) was recent approved by FDA for wild metastatic NSCLC expressing PD-L1 ≥ 1%. Best results were obtained in patients expressing PD-L1 ≥ 50 %, reaching a median overall survival of 21 months, which was significantly better than the median overall survival of 14 months achieved with chemotherapy. In a wild metastatic NSCLC without rapidly progressive disease and higher than 50% PD-L1 expression, pembrolizumab (MoAb anti-PD1) monotherapy has been associated with an improved median overall survival of 30 months. Patients showing rapidly progressive disease and low expression of PD-L1 should be better treated with a combination of chemotherapy + immunotherapy. Under this circumstance, morphologic phenotype should orient treatment decision-making. Non-squamous cell histology favors the combination of pembrolizumab with the doublet pemetrexede + carboplatin, while in squamous cell histology pembrolizumab is better combined with the doublet carboplatin + paclitaxel / nab-paclitaxel. These therapeutic options cover treatment recommendation for wild metastatic NSCLC, which are not candidates for targeted therapy. Improved results observed in the treatment of metastatic NSCLC will lead to a possible disease chronification. Knowledge translation and well-designed clinical trials will be responsible for the expected reduction in the gross lung cancer mortality rate.

CMR = Crude Mortality Rate, IARC = International Agency for Research on Cancer, MRD = Median Response Duration, EGFR = Epidermal Growth Factor Receptor, TKI = Tyrosine Kinase Inhibitor, FDA = Food & Drug Administration



1.     International Agency for Research on Cancer, World Health Organization, 2018 

2.     Soria JC, Ohe Y, Vansteenkiste J, et al: Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer, N Engl J Med 378(2): 113, 2018

3.     Anita Midha, Simon Dearden and Rose McCormack: EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII), Am J Cancer Res 5(9):2892-2911, 2015

4.     Jose M. Pacheco, Dexiang Gao, Derek Smith, et al: Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non–Small Cell Lung Cancer, J Thor Oncol 14: 691 – 700, 2019

5.     Drilon A, Siena S, Dziadziuszko R, et al: Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials, Lancet Oncol 21(2):261, 2019

6.     Koichi Goto, Geoffrey Oxnard, Daniel Shao-Weng Tan, et al: Selpercatinib (LOXO-292) in patients with RET-fusion+ non-small cell lung cancer, J Clin Oncol 38 (15): 3584, 2020

7.     Lucy S. K. Walker & David M. Sansom: The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses, Nat Rev Immunol 11: 852 – 863, 2011

8.     Suzanne L. Topalian, Charles G. Drake and Drew M. Pardoll: Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity, Curr Opin Immunol 24(2): 207 – 212, 2012

9.     Hellmann MD, Paz-Ares L, Bernabe Caro R: Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer, N Engl J Med 381:2020-203, 2019

10.  Tony S K Mok, Yi-Long Wu, Iveta Kudaba, et al: Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial, Lancet 393: 1819–30, 2019

11.  Photo by Simon Connellan on Unsplash