A new era of targeted therapy for lung cancer

Toronto–It was only as far back as the 1990s that lung cancers were all thought to be the same disease and treatment consisted of the same platinum-based chemotherapy. Now, it's known non-small lung cancers (NSLC), which account for 85% of lung cancers, are not all the same, and the era of targeted therapies has begun with new therapies still emerging. Currently, lung cancer is the most commonly diagnosed cancer in Canada, leading to 30,000 new cases yearly. It is the leading cause of death from cancer, about 70% of patients are diagnosed at either stage III or IV, and the five-year survival rate is 19%, according to Dr. Catherine Labbé, head of the respiratory medicine service at Institut Universitaire de Cardiologie et de Pneumologie de Quebec. She spoke at the annual (virtual) conference of the Canadian Thoracic Society earlier this year where she gave an overview of advances in using tyrosine kinase inhibitors (TKIs) and immunotherapy for non-small cell lung cancer (NSCLC). “Today, patients are treated with personalized therapy based on histology and biomarker test results. Genetic alterations, that are oncogenic drivers, are found in a higher percentage of lung adenocarcinomas than in squamous cell carcinomas or other histologic subtypes,” she said. Patients who receive therapies which target specific genomic alterations tend to have better responses, improved quality of life and improved survival over traditional chemotherapy, she said. READ: Study shows immunotherapy extends disease-free survival in post-surgery kidney cancer patients Shortly after the new millennium began, researchers found that NSCLC and small-cell lung cancer were different in terms of prognosis and how they responded to treatments. Then it was found there were subtypes of NSCLCs which opened the door to new targets for treatment. In the early 2000s, patients with mutations in the epidermal growth factor receptor (EGFR—a part of cells that affects cell growth and survival), were found to have a clinical response to gefitinib—a TKI. This heralded big changes in lung cancer treatment. Now, there are inhibitors that are widely used and available for patients who have specific mutations in the EGFR, ALK, RET, BRAF, ROS1, NTRKm, MET and KRAS genes. Mutations in KRAS make up about 25% of the NSCLC population; EGFR mutations occur in 17%, ALK mutations occur in about 7%, and each of the other mutations drive cancer in about 1% to 4% of patients. About 31% of patients have unknown oncogenic drivers. With the newer treatments, “There’s hope for patients, even with advanced disease,” she said. An example lay in the final results published in 2018 from the phase III PROFILE 1014 trial which compared crizotinib (an ALK inhibitor) with chemotherapy as first-line treatment. Survival at four years was 56.6% with crizotinib versus 49.1% with chemotherapy. The difference might not seem important, but the majority of patients in the chemotherapy group received crizotinib when their disease progressed, she said. Now “when I see a patient with newly diagnosed stage IV NSCLC with an ALK rearrangement, I can say that he or she has around a 50% chance of still being alive at four years,” Dr. Labbé said. Third generation TKIs The first generation TKIs such as crizotinib or gefitinib have been used for years, but there are also third generation TKIs such as osimertinib which target specific EGFR mutations. In one study, osimertinib showed a significant benefit over gefitinib or erlotinib as first-line treatment. Another big advance occurred in 2020 when the Codebreak100 trial showed significant anticancer activity in patients with KRAS G12C gene mutations when given sotorasib. These patients, generally are resistant to targeted therapies, and have poor outcomes. It was approved this summer by the FDA in the U.S. and is under review by Health Canada. This “can be literally qualified as a triumph of drug discovery,” Dr. Labbé said. All patients with stage IV nonsquamous NSCLC should be tested for biomarkers regardless of smoking status. Targeted therapies against EGFR and ALK should be offered to patients as first-line therapy. Targeted therapies against ROS-1, BRAF V600e, RET, MET, NTRK should be offered to appropriate patients as first or second-line therapy, she said. But what about patients with early-stage disease? Dr. Labbé noted that the ADAURA phase-3 trial found that patients with stage Ib to IIIa completely resected NSCLC, with an EGFR mutation, had significantly longer disease-free survival with osimertinib as adjuvant therapy after chemotherapy when compared to placebo. But even patients who did not undergo chemotherapy had improvement. “All patients with resected adenocarcinoma or adenosquamous carcinoma should be tested for EGFR and should be offered osimertinib if mutated,” she said. Osimertinib was approved by Health Canada for this indication in January 2021. This treatment is now part of the National Comprehensive Cancer Network (NCCN) Guidelines. The standard of care has also changed for stage IV patients who lack the known cancer-driving mutations. “They are now all eligible to receive immunotherapy in the first-line setting,” she said. The Keynote 024 trial was the first to show superiority of immunotherapy as a monotherapy over chemotherapy in the first-line setting. The study included patients with untreated stage IV NSCLC, regardless of histology. Patients were included if they had a PD-L1 of at least 50%. Patients were randomized to receive either standard chemotherapy, or the checkpoint inhibitor pembrolizumab. Overall survival was double at five years among those given pembrolizumab (32%) compared to chemotherapy (16%). Other studies show that the combination of chemotherapy and immunotherapy improves survival in patients with untreated nonsquamous and squamous stage IV NSCLC, regardless of PD-L1 level. “All patients with advanced NSCLC should be tested for driver alterations (mutations), as receiving matched targeted therapies improves response rates, progression-free survival, quality of life and, often, overall survival. Patients with resected adenocarcinoma or adenosquamous carcinoma should be tested for EGFR and should be offered osimertinib, if mutated. Immunotherapy is a standard of care after concurrent chemotherapy and radiation for locally-advanced, unresectable NSCLC, as shown in the Pacific trial. And, immunotherapy can be offered to all patients with non-mutated stage IV NSCLC in the first-line setting, either as a monotherapy or in combination,” she said.

A new era of targeted therapy for lung cancer

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