Osimertinib, gefitinib combination tolerated in EGFR-mutated NSCLC
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In the first-line setting, osimertinib and gefitinib as combination therapy for the treatment of EGFR-mutated non-small cell lung cancer is tolerable, according to findings presented at the virtual ASCO annual meeting.
“The most important takeaway is discussing the tolerability of the combination,” Julia K. Rotow, MD, medical oncologist at the Dana-Farber Cancer Institute, told Healio. “This abstract adds to our understanding of the safety around that combination.”
According to the abstract, osimertinib (Tagrisso, AstraZeneca) is active against the acquired gefitinib-resistant mutation EGFR T790M, while gefitinib (Iressa, AstraZeneca) is active against the osimertinib-resistant EGFR C797S, and some preclinical evidence suggests that the emergence of acquired resistance may be delayed by treating with a dual combination of osimertinib and gefitinib.
Between May 2017 and July 2019, researchers enrolled 27 patients with stage IV EGFR-mutated (L858R or del19) non-small cell lung cancer (NSCLC) who did not receive prior therapy for metastatic disease in this ongoing phase 1/2 study. According to the abstract, six patients received dose escalation treatment of concurrent 40 mg or 80 mg osimertinib plus 250 mg gefitinib, daily. Concurrently, 21 patients received dose expansion treatment of osimertinib + gefitinib at the maximum tolerated dose (MTD), which was reported to be daily oral administration of 80 mg osimertinib plus 250 mg gefitinib. The researchers defined feasibility as the receipt of combination therapy for 6 or more 4-week cycles.
Rotow and colleagues reported 81.5% of patients completed 6 or more cycles of combination therapy. However, one patient discontinued due to progression and four patients due to toxicity. The overall response rate was 88.9% (95% CI, 71.9%-96.1%), while the best response was an 88.9% partial response and 11.1% stable disease.
“We did find that the adverse events we observed were consistent with the known toxicity profiles of EGFR TKIs, certainly at a higher rate as you might expect with a combination therapy,” Rotow said. “But overall, they were grade 1 and grade 2 in severity, which is reassuring for use of this combination going forward.”
Rash, diarrhea and dry skin were the most common treatment-related adverse events.
“One very interesting component of this presentation is looking at plasma for EGFR C797S clearance and how that might relate to outcomes,” Rotow explained. “There is a theoretical belief that rapid clearance of the EGFR mutation from plasma may correlate with better outcomes for patients.”
Using cell free DNA by droplet digital PCR (ddPCR), the researchers tested 25 patients for the EGFR driver mutation at baseline. The driver mutation was detected in 65% of patients, and after 2 weeks of treatment plasma EGFR cleared to undetectable in 88% of patients.
“Next steps involving this particular combination is continuing our trial enrollment and obtaining full matured data analyses to better understand whether combination therapy upfront serves as a disease modifying therapy in a way that might effect ongoing progression free survival for patients, which is perhaps the most meaningful outcome even beyond response rates for this combination,” Rotow said. “Understanding how upfront therapy may affect observed resistance mechanisms is also critical because for patients, subsequent resistance does drive what their combination therapy or non-targeted therapy options may be.”
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Rotow JK, et al. Abstract 9507. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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