One affirms single-agent EGFR TKI treatment, such as with osimertinib, as the current standard of care for first-line advanced metastatic EGFR-positive mNSCLC, and the other affirms clear benefits for first-generation EGFR TKIs combined with either chemotherapy or VEGF monoclonal antibodies.
In the analysis supporting combination therapy for mNSCLC, Sara Moore, MD, and Paul Wheatley-Price MD, wrote that while targeted therapy with EGFR TKIs is highly effective initially, resistance inevitably develops.
Recent data, they stated, have demonstrated that combination strategies can delay development of resistance and improve outcomes for mNSCLC populations. Combining first-generation EGFR TKIs with either chemotherapy or VEGF monoclonal antibodies has led to consistent improvement in progression-free survival (PFS) and overall survival (OS) in some cases. In the NEJ009 trial, the combination of chemotherapy (carboplatin and pemetrexed, with pemetrexed maintenance) plus gefitinib versus gefitinib alone improved response rate (84% vs. 67%, P < 0.001), PFS (median, 20.9 months vs. 11.2 months; P < .001), and OS (median, 50.9 months vs. 38.8 months; P = .021). An increase in adverse events in the chemotherapy arm led to a decrease in quality of life.
Another clinical trial (by Noronha and colleagues) conducted in India of the same combination found benefit for combination therapy in response rate (75% vs. 63%), PFS (median, 16 months vs. 8 months), and OS (not reached vs. 17 months). Grade 3 or higher adverse event rates were higher with the combination (51% vs. 25%) with quality of life was not yet reported.
While both trials have been criticized owing to a lack of standard T790M resistance testing and low use of osimertinib in subsequent lines of therapy, Dr. Moore and Dr. Wheatley-Price pointed out: “Even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”
The importance of using combination therapy in the first-line setting, they stated, is underscored by the consistent drop-off in patients who receive second-line combination therapy. In the phase 3 FLAURA trial of first-line osimertinib monotherapy, of the patients who discontinued osimertinib, the most common reason for not receiving subsequent therapy was death (60% went on to receive further systemic therapy). This highlights the need to use the most effective treatments up front, Dr. Moore and Dr. Wheatley-Price wrote.
The four large trials of VEGF-targeted therapy with either monoclonal antibodies or TKIs added to first-generation EGFR TKIs have consistently shown improved PFS. Increased toxicities led to discontinuation of VEGF-targeted therapy in 20%-30%.
In the RELAY trial, however, despite more toxicities, quality of life was not diminished. In general, the authors concluded that long-term detriments to quality of life have not been demonstrated. Ongoing studies of osimertinib in combination with VEGF inhibition include a phase 1/2 trial with bevacizumab in previously untreated patients showing an 80% response rate (median PFS, 18.4 months) with no unexpected toxicity.
Chemotherapy-based treatment for mNSCLC with third-generation EGFR TKIs, in appropriately selected patients, the authors concluded, “can offer an additional standard-of-care option as first-line treatment of EGFR-mutant lung cancer.”
Since the introduction of EGFR TKIs, Sophie Stock-Martineau, MD and Frances A. Shepherd, MD noted in their analysis, researchers have aimed to improve their efficacy through combining them with other agents. The authors review research on the addition of chemo- or immunotherapy and agents targeting major resistance mechanisms such as MET. Their review of the same NEJ009 trial focuses, however, on the 65.3% (EGFR TKI plus chemotherapy) versus 31.0% (gefitinib alone) grade 3 adverse event rate, and the 51% versus 25% grade 3 adverse event rate in a similar trial by Noronha and colleagues. The review by Dr. Stock-Martineau and Dr. Shepherd further found that, while adding antiangiogenic agents to an EGFR TKI “mildly” prolongs PFS, survival benefits have not been demonstrated. The added costs, not just in toxicity, were a “far from negligible” $120,000 above the cost of bevacizumab alone for 16 treatments. Data from trials of immune checkpoint inhibitors added to EGFR TKIs reveal heightened toxicities and limited efficacy. Trials of EGFR monoclonal antibodies with an EGFR TKI showed no PFS or OS benefit and were terminated early. Similarly, evidence to date shows no benefit beyond that shown for EGFR TKI monotherapy with the addition of a MET inhibitor.
“Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system,” Dr. Stock-Martineau and Dr. Shepherd concluded, further observing that combinations, given their heightened toxicity profiles, could potentially also worsen quality of life.
No conflicts of interest were reported by the authors of either study.
