AACR 2020 Conference – Advances in the Field of Lung Cancer Targeted Therapies
By Ruchi Jhonsa, Ph.D.
Killing over 1.7 million people in 2018, lung cancer remains one of the most deadly and common types of cancer in the world. Traditionally, lung cancer was treated either by invasive surgical procedures or by application of platinum-based chemotherapeutic agents, but with the advent of genomic medicine and advances in the knowledge of pathways driving cancer, targeted therapies and immunotherapies have been developed to combat the problem.
Targeted therapies like EGFR inhibitors erlotinib, gefitinib, AKT inhibitor everolimus, and NTRK/ROS1 inhibitor entrectinib along with anti-PD-1/PD-L1 immunotherapies have been hugely successful in treating lung cancer and have become the standard of care treatment for many types. Despite these advances, challenges like tumor resistance demand new studies and development of novel therapies to tackle the disease. The lung cancer target therapies session at the virtual AACR touched upon some of the recent developments in the field.
Tyrosine Kinase Inhibitor, Capmatinib Resolves Brain Lesions
Reported in 3-4% of patients with non-small cell lung cancer, somatic MET mutations are emerging as important driver mutations for lung cancers. Patients who harbor this mutation have a poor prognosis and are generally non-responsive to standard therapies, including immunotherapy. Several MET targeted tyrosine kinase inhibitors (TKIs) are being investigated clinically for these patients, including crizotinib, cabozantinib, tepotinib, and savolitinib. However, their clinical response has been disappointing.
The collaborative study, GEOMETRY mono-1 presented at AACR in the afternoon session on day 1, evaluated the efficacy and safety of capmatinib, a MET targeted TKI in treatment-naïve and pretreated patient cohorts with advanced or brain metastasized NSCLC harboring METex14 skipping mutations. BIRC evaluation of the drug reported clinically meaningful efficacy in both the cohorts with an objective response rate of 67.9% in treatment-naïve and 40.6% in pretreated patients. In addition to the significant systemic effects, the drug also showed a positive impact on brain lesions. Of the 13 evaluable patients with brain metastasis, 7 showed intracranial response out of which 4 showed complete resolution of all the brain lesions, and 3 showed partial resolution. Overall, the drug showed deep and durable responses in patients with the specific MET mutation with a manageable safety profile.
Pembrolizumab Monotherapy Works Regardless of STK11 or KEAP1 Status
Pembrolizumab, Merck’s blockbuster drug, has become a star therapy for treating PD-L1 expressing NSCLC in the past years. First shown in the KEYNOTE-001 clinical trial, the drug had an overall response rate of 20% among previously treated and treatment-naïve patients with advanced NSCLC. However, a 2018 study from the group of Dr. Ferdinandos Skoulidis, M.D., Ph.D. MD Anderson Cancer Center, showed that action of immunotherapy on cancer cells could be thwarted by the presence of STK11/LKB1 mutations in the genome bringing down the overall response rate from 20% to mere 8%.
Challenging this notion, the exploratory analysis of KEYNOTE-042 presented by Dr. Byoung Cho from Yonsei University Cancer Center at the AACR virtual meeting today showed that pembrolizumab monotherapy works well for treating NSCLC regardless of the genetic alterations in STK11 and KEAP1 gene. The ORR (31%) and OS (18 months) with pembrolizumab determined by the study were similar in patients with or without STK11 or KEAP1.
However, the stark contrast in the results of this study to the previous report from Dr. Skoulidis group that showed a significant drop in the ORR and OS in patients harboring STK11 and KEAP1 mutations could be due to the limited number of patients with a modest frequency of STK11 and KEAP1 mutations in the study. Looking at the data, Dr. Skoulidis advised that although “intriguing,” the results of this study should be taken with a pinch of salt.
The Safety Profile of 3Ps
For NSCLC patients, cytotoxic chemotherapy is usually the first line of treatment. However, in advanced cases, modulation of the immune response through PD-1 inhibition right from the start is considered as an effective treatment. The KEYNOTE-189 trial led to the establishment of chemo-immunotherapy with the trio of pemetrexed, platinum, and pembrolizumab as a standard of care for the first-line treatment for the patients with nonsquamous NSCLC.
The KEYNOTE-189 study also laid out details of treatment during maintenance, which included dosing with the combo of pemetrexed and pembrolizumab. However, data from Flatiron Health’s database showed that about half of the practitioners switch to using pembrolizumab alone during maintenance rather than the recommended combination. It is believed that this clinically unproven idea is merely a perceived toxicity concern of maintenance combo that comes either from the practitioner or patient during the treatment.
The study conducted jointly by the researchers from UCLA, Eli Lilly, and the University of Michigan addressed this concern and evaluated the toxicities of the treatment specific to the maintenance period in the two arms of the KEYNOTE-189 trial. They determined that the majority of the adverse events, including nausea and fatigue occurred within the three months from the first dose, which is when most of the patients discontinued from the recommended maintenance treatment. However, the AE’s resolved within two weeks from the time of their onset. Overall, the study suggests the recommended treatment of pemetrexed and pembrolizumab is safe and can be used for the long term with manageable toxicity.
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