Presentation by Dr Jaime Schneider, MD PhD, Massachusetts General Hospital
At the 2023 Total Health Best of Lung conference held in Manalapan, Florida Dr. Jaime Schneider from Massachusetts General Hospital presented on the topic of using targeted therapies in patients with non-small cell lung cancer (NSCLC). Lung cancer remains the leading cause of cancer related deaths worldwide, and patients are unfortunately most often diagnosed at an advanced stage, when curative approaches are no longer feasible. NSCLC is the most common subtype of lung cancer (~85% of patients) and the use of targeted therapies in NSCLC relies on the identification of specific molecular alterations (mutations) in the patient’s genetic tumor profile that enable an uncontrolled proliferation of the tumor cells, also known as a “driver mutations”. These alterations can be identified by a molecular analysis (using next-generation sequencing, or ‘NGS’) of the patient’s tumor sample, which is generally obtained with a tissue biopsy. There are a range of effective and well-tolerated targeted treatments now approved and available for use in NSCLC that are specifically designed to inhibit the growth of tumor cells that harbor a given driver mutation. As such, it is becoming increasingly important that patients with newly diagnosed NSCLC undergo NGS testing, to determine if they are candidates for treatment with these therapies.
Dr Schneider reviewed the historical standard of care (SOC) treatment for patients with advanced (Stage IV) lung cancer, which was generally chemotherapy doublet (two therapy) regimens, specifically platinum doublet regimens (e.g., cisplatin and docetaxel, carboplatin and paclitaxel) which resulted in uniformly poor time to progression (TTP) outcomes, on the order of several months. In 2006, it was found that the addition of another targeted agent called bevacizumab (Avastin) to these chemotherapy regimens could improve survival by a small but statistically significant degree. Over the last 10 to 15 years, however, Dr Schneider noted a rapid pace of regulatory approvals in NSCLC, beginning with the approval of targeted treatments for NSCLC tumors harboring specific molecular alterations (also called ‘biomarkers’) in genes such as anaplastic lymphoma kinase gene (ALK) and epidermal growth factor receptor (EGFR). Targeted treatments are generally small molecule compounds, such as tyrosine kinase inhibitors (TKIs) which act to inhibit a specific molecule (usually a kinase) which the patient’s tumor is dependent upon in order to grow. When a patient’s tumor harbors such a molecular alteration, identified through the use of NGS testing, this is referred to as an ‘actionable’ driver mutation, or one that can be inhibited with a specific targeted therapy. The availability of targeted therapy has had a tremendous impact on NSCLC treatment, as many of these agents are now indicated in the first line (1L) setting for patients with advanced or metastatic disease, where, historically, chemotherapy would have been the only treatment option. In this regard, Dr Schneider reviewed the current standard treatment algorithm for an advanced, non-squamous NSCLC patient, which would be a biopsy of the surgical tumor specimen, followed by NGS testing to determine whether the patient has an actionable driver mutation and is a candidate for 1L targeted therapy.
EGFR-Directed Targeted Therapy
Dr Schneider gave an example of a patient (55 year old, Asian, non-smoker) presenting with symptoms of shortness of breath (dyspnea) on exertion, a dry cough, and fatigue, who was subsequently diagnosed with advanced EGFR-mutant (L858R) NSCLC. She noted that within 6 weeks of beginning treatment with an advanced, 3rd generation EGFR inhibitor targeted therapy (Osimertinib), the patient had an excellent response, with significant improvement in her symptoms and a marked reduction in tumor size on radiographic imaging. She further noted results from several phase III clinical trials comparing 1L EGFR-targeted therapies with standard of care chemotherapy, all of which demonstrated the superiority of targeted therapy over 1L chemotherapy. The results of these trials caused a fundamental shift in the treatment paradigm, such that targeted therapies became the preferred treatment option in the first line setting. Dr Schneider also highlighted the progression of EGFR-targeted TKI treatments (Box 1) from first generation drugs, which were inhibitory for both the normal (wild type) as well as the mutant EGFR (resulting in more toxicity/adverse events), to the third generation, ‘irreversible’ type TKIs (e.g., Osimertinib) which much more selectively and specifically inhibit the mutant EGFR, and are also active for the more treatment-resistant alterations, such as T790M mutation. Dr Schneider noted that Osimertinib was initially approved for use in the 2nd-line setting for patients who had previously received a first generation EGFR-targeted therapy and had developed a resistance on the basis of a T790M mutation. A subsequent seminal Phase III trial (FLAURA) examined the use of Osimertinib in the 1L setting, as compared to a first generation drug (gefitinib or erlotinib) and also showed a significant benefit in progression-free survival (PFS) for patients receiving Osimertinib (18.9 months versus 10.2 months; hazard ratio [HR] = 0.46; P<0.0001). Results from FLAURA thus established Osimertinib as the standard of care for 1L therapy in patients with EGFR mutant NSCLC.
Box 1. Evolution of EGFR-Directed Therapies in NSCLC
Despite the efficacy of EGFR TKIs, however, Dr Schneider noted that acquired resistance to these targeted therapies occurs, through a variety of mechanisms, for example, another EGFR mutation, or an alternative pathway for growth may emerge that is no longer sensitive to inhibition by the treatment; another possibility is what is known as histologic transformation of the cancer from a non-small cell to small cell subtype which may have additional molecular alterations that are not sensitive to the treatment. As such, despite their initial efficacy, these targeted therapies are not “curative” treatments per se, and an active area of research is therefore what to do when patients progress on Osimertinib in the first line. For example, many patients who become resistant to EGFR TKI therapies develop amplification of the MET gene, and trials such as TATTON have examined the use of Osimertinib in combination with a MET inhibitor (salvolitinib). In this regard, patients should also be tested by NGS at the time they develop resistance to EGFR treatment.
Lastly, on the topic of EGFR TKIs, Dr Schneider highlighted the results from the Phase III ADAURA trial, which examined the use of Osimertinib in the adjuvant (post-surgical) setting. The results of ADAURA clearly showed a benefit in disease-free survival (DFS) for patients in Osimertinib versus placebo (36 months DFS, 80% vs. 28%; HR=0.17; P<0.0001), which resulted in its approval by the US Food and Drug Administration (FDA) for the adjuvant treatment of patients with surgically resected Stage II to IIIA NSCLC having EGFR Exon 19 deletions or L858R mutations. Importantly, patients on Osimertinib also had an overall survival (OS) benefit, with a 5-year OS of 85% versus 73% (HR=0.49; P<0.001).
Rearrangements in the ALK gene occur in about 5 to 7% of all NSCLC cases, and these ALK+ patients are usually younger, with a light or no smoking history and have adenocarcinoma histology. A total of 5 ALK-targeted therapies have been approved since 2011, and patients with ALK+ NSCLC are highly sensitive to ALK inhibition with drugs such as crizotinib with good response rates. Like the EGFR-targeted therapies, ALK inhibitors have also progressed from 1st generation TKIs to 3rd generation TKIs (Box 2), resulting in better specificity for the ALK target, better efficacy for patients with secondary ALK-resistance mutations, and, importantly, better penetrance of the drug into the central nervous system (CNS), which is important for treating patients whose disease has spread to the brain. Trials such as CROWN, comparing 1st versus 3rd-generation ALK inhibitors (lorlatinib versus crizotinib) have shown significant improvement in PFS, with a 12-month PFS rate of 78% versus 39%, and ongoing results continue to suggest a strong benefit of lorlatinib in this setting (HR= 0.28; P<0.001). Also, similar to the EGFR TKIs, efforts are underway to move the ALK inhibitors earlier in the course of treatment.
Box 2. Evolution of ALK-Directed Therapies in NSCLC
Other Targeted Therapies
Some of the other molecular alterations in NSCLC, and the corresponding targeted treatment options that are currently available, are summarized in Box 3. These include ROS1, RET, TRK, MET exon 14 skipping, BRAF V600E and KRAS G12C. Many of these therapies have shown efficacy in both untreated (treatment-naïve) as well as previously treated NSCLC, and other benefits such as enhanced CNS penetrance for treating brain metastases. The availability of these targeted therapies and their potential benefit over previous standard of care treatments such as chemotherapy in patients with NSCLC underscores the need for early and comprehensive NGS testing, to identify which patients may be candidates for treatment, and with which therapy.
Box 3. Other NSCLC Driver Mutations and Their Targeted Treatments
MET exon 14 Skipping
Dabrafenib + Trametinib
Summarizing her presentation, Dr Schneider noted that targeted therapies are significantly improving survival and the overall prognostic landscape in advanced NSCLC. At the same time, the use of these therapies has necessitated a fundamental change in the way patients are diagnosed and treated, with a critical role for NGS testing, in order to identify opportunities for targeted therapy as early as possible. At present, targeted treatments for patients with EGFR, ALK, ROS1, NTRK, BRAF V600E, RET, MET exon 14 skipping, and KRASG12C molecular alterations are available, with many other driver mutations and therapy options under investigation in ongoing clinical trials. Efforts also continue to move these targeted therapies to earlier stages in NSCLC to further improve outcomes.
Speaker Disclosure Information: Dr Schneider reported the following disclosures for this presentation: Honorarium: Academy of Continued Healthcare Learning, Springer Healthcare, Targeted Oncology; Institutional Research Funding: American Cancer Society (MGH IRG); Research Funding: A Breath of Hope Lung Foundation, Lung Cancer Research Foundation/ALK Positive
You can view the full presentation from the Total Health 2023 Best of Lung Conference here: