Immunotherapy for patients with metastatic NSCLC harboring an EGFR mutation
Management of non-small-cell lung cancer (NSCLC) has dramatically changed in the last decade. Due to an improved understanding of the molecular biology of NSCLC, we are now able to offer personalized treatment approaches, including targeted therapies for a subset of patients who harbor activating mutations. Through mutation testing of patients, we can better select therapies and improve outcomes, heralding an era of precision medicine for this deadly disease . A prime example of this improvement has been in the subset of patients who have a sensitizing mutation in the EGFR gene, which can be specifically targeted with tyrosine kinase inhibitors (TKIs). We now have five EGFR-targeted, FDA-approved agents for this subset alone: first-generation TKIs erlotinib and gefitinib, second-generation TKI afatinib, third-generation TKI osimertinib, and most recently, another second-generation TKI dacomitinib.
The success of targeted therapy
Multiple randomized studies have established oral EGFR-targeted therapeutic approaches as superior to chemotherapy in NSCLC patients with EGFR mutations . Based on this significant improvement, our current standard of care involves the use of molecular testing upon initial diagnosis for non-squamous NSCLC patients. Given that we now have so many options for frontline use, we must choose wisely. There are several factors influencing therapy selection in the frontline setting, including the degree of overall survival benefit, tolerability of the drug, quality of life, and benefit in the setting of intracranial metastases. It is important to remember that some patients may never make it to second-line therapy so it is crucial to select the best therapeutic approach first.
The FLAURA trial has clearly established osimertinib as the current standard for treatment of patients in the frontline setting. It has a clear progression-free survival (PFS) benefit, reduces the incidence as well as emergence of CNS metastases, is very well-tolerated, and promises a good quality of life [3,4]. Another potential option is dacomitinib, which was recently approved by the FDA for frontline treatment of patients with metastatic NSCLC harboring an EGFR mutation in exons 19 or 21 based on the ARCHER 1050 study . However, even though dacomitinib appears promising, it was compared to gefitinib, which is currently not a standard of care first-line therapy. Dacomitinib also has significant toxicity, so it is not clear how it will fit into the current treatment paradigm.
Where does immunotherapy fit in?
Despite the excitement generated by immunotherapy and its increasingly prominent role in treating advanced NSCLC, it has had less success in the subset of EGFR mutation-positive patients. For example, pembrolizumab was recently evaluated in patients with metastatic EGFR-mutant NSCLC . Patients with a programmed cell death ligand 1 (PD-L1) PD-L1 tumor proportion score (TPS) of at least 1% received pembrolizumab at 200 mg iv every 3 weeks, and they were treated with 35 study infusions or until disease progression. The primary objective was overall response rate (ORR) to immunotherapy prior to TKI use. However, the trial was closed early, after 11 of the target 25 patients were enrolled, owing to a lack of efficacy despite the majority of the patients having high PD-L1 expression (TPS≥50%). Only one patient had an objective response, but repeat analysis of this patient’s tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events (AEs) were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern and led to the trial being suspended.
What about combination therapy?
Whether a combination of EGFR-TKIs and immunotherapy could be another promising approach remains to be seen. Osimertinib has been studied in combination with the anti-PD-L1 antibody, durvalumab; however, the combination was also associated with high rate of pneumonitis, with poor ORR . At the IASLC 19th World Conference on Lung Cancer 2018, we saw results from a phase Ib safety trial of a combination of erlotinib and atezolizumab: 28 patients were enrolled and no grade 5 AEs were reported . ORR was 75%, with a median duration of response of 19 months. Interestingly, biomarker analyses revealed increased PD-L1 expression and CD8+ T-cell tumor infiltration in some patients after EGFR-TKI therapy. Further investigation of this combination is warranted.
Should patients with high PD-L1-expressing tumors be treated with immunotherapy preferentially?
Based on the phase II data on single-agent pembrolizumab for these patients, the answer would be no. Additionally, PD-L1 expression was evaluated in the FLAURA trial . Of the 994 patients who were screened for enrollment, PD-L1 testing results were available for 128 patients; 106 patients were randomized to treatment, of whom 54 received osimertinib. In this subset analysis, use of EGFR-directed therapy with osimertinib was associated with a sustained PFS benefit amongst patients with varying levels of PD-L1 expression, including patients with PD-L1- negative and -positive disease; median PFS in the osimertinib group was 18.4 months for patients with PD-L1 expression greater than 1%, and 18.9 months for PD-L1-negative patients.
This study tells us two things: firstly, it shows us that PD-L1 expression may be high in patients with EGFR-mutant NSCLC; of all of the available 128 EGFR-mutant patients, 65 had PD-L1 expression greater than 1%. Secondly, this sub-analysis confirms that standard of care first-line therapy for EGFR-mutant patients should still be targeted therapy, based on this sustained PFS improvement irrespective of PD-L1 status.
In summary, targeted therapy, and in particular osimertinib, remains our standard approach for first-line therapy in EGFR-mutant NSCLC. Immunotherapy alone administered in an unselected fashion in patients with EGFR-mutant NSCLC may lead to worse outcomes including significant toxicity, and should be carefully evaluated in the clinical trial setting. At this time, there is no clearly defined role for frontline use of immunotherapy for patients with actionable mutations and we should avoid using immunotherapy alone for these patients, even those with high PD-L1 expression. Results from the IMPower150 trial showed that addition of bevacizumab to atezolizumab and chemotherapy prolonged survival for EGFR-mutant/ALK-rearranged patients, with a hazard ratio of 0.54, compared with bevacizumab and chemotherapy alone . However, these were small numbers, and subset analyses of a large trial. These data alone are probably not enough to change practice, but they raise an interesting question of whether anti-angiogenic therapy can be added to chemotherapy and immunotherapy for the management of patients progressing following TKI treatment. In the future, we look forward to using combination therapies, including chemotherapy with TKIs, as well as a combination of active TKIs with angiogenesis inhibitors.
Charu Aggarwal is a member of the Academic Thoracic Oncology Medical Investigator’s Consortium’ (ATOMIC)
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