As of November 2022, osimertinib is the preferred choice for the frontline treatment of EGFR-mutated non-small cell lung cancer. However, some experts believe that combination chemotherapy plus EGFR TKI will become a standard frontline treatment.
For patients with EGFR-mutated non–small cell lung cancer (NSCLC), osimertinib (Tagrisso) continues to be the preferred frontline therapy, according to Zosia Piotrowska, MD, MHS.1
However, for those with classic EGFR mutations, exon 19 deletions, and L858R substitutions, she believes the day is fast approaching when physicians will add chemotherapy to first-line treatment with the EGFR TKI based on circulating tumor (ct)DNA results. Piotrowska, an assistant professor of medicine at Harvard Medical School and an attending physician at Massachusetts General Hospital, noted that there is subgroup of persister cells that osimertinib cannot eradicate that chemotherapy may be able to target. Furthermore, reserving chemotherapy is suboptimal because many patients never proceed to second-line treatment.
“We know that chemotherapy is an effective strategy for these patients,” she said. “So perhaps they’ll do better if we give them both up front.”
Data from 2 phase 3 trials, NEJ009 from Japan and a trial from India comparing gefitinib (Iressa) with gefitinib plus pemetrexed (Alimta) and carboplatin chemotherapy, have demonstrated a survival benefit from adding chemotherapy to a TKI.
In the Indian trial, patients with advanced NSCLC harboring an EGFR-sensitizing mutation and an ECOG performance status of 0 to 2 were randomly assigned to gefitinib 250 mg orally per day (n = 176) or gefitinib plus pemetrexed 500 mg/m2 and carboplatin area under curve (AUC) 5 intravenously (IV) every 3 weeks for 4 cycles, followed by maintenance pemetrexed (n = 174). Eighteen percent of patients had brain metastases. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate, and toxicity.2
At a median follow-up of 17 months (range, 7-30), the radiologic response rate was 75% in the combination arm vs 63% in the monotherapy arms. (P = .01). The estimated median PFS was 16 months (95% CI, 13.5-18.5) with the combination vs 8 months (95% CI, 7.0-9.0) with the monotherapy (HR for disease progression or death, 0.51; 95% CI, 0.39-0.66; P <.001). The estimated median OS also favored the combination (not reached vs 17 months; hazard ratio for death, 0.45; 95% CI, 0.31-0.65; P <.001).
In NEJ009, investigators enrolled patients aged 20 to 75 years with chemotherapy-naïve stage IIIB or IV or relapsed nonsquamous NSCLC harboring EGFR mutations. Patients were also required to have an ECOG performance status of 0 or 1, plus adequate organ function.
All patients received 250 mg of oral gefitinib once per day. Patients in the combination arm also received carboplatin AUC 5 and 500 mg/m2 of pemetrexed in a 3-week cycle for up to 6 cycles, followed by concurrent gefitinib and pemetrexed maintenance. If patients in the combination arm were intolerant of gefitinib or chemotherapy, they were permitted to continue treatment on the remaining agents.
Updated data published in 2022 showed that, in the combination arm, the mean OS, 2-year OS rate, and 5-year OS rate were 49.0 months, 77.1%, and 39%, respectively. Those data were 38.5 months, 69%, and 34%, respectively, in the gefitinib arm (HR, 0.822; 95% CI, 0.639-1.058; P = .127).3
Benefit in time to second progression (PFS2) data showed that patients treated with gefitinib plus chemotherapy (n = 169) achieved a corrected median PFS2 of 20.9 months (95% CI, 18.0-24.0) compared with 18.0 months (95% CI, 16.3-20.7) for patients treated with gefitinib alone (n = 172; HR, 0.77; 95% CI, 0.62-0.97; P = .027).
An additional analysis of PFS2 with the same definition showed that the updated median PFS2 was 32.5 months (95% CI, 29.0-36.6) for the gefitinib plus chemotherapy group vs 20.7 months (95% CI, 17.9-24.6) for the gefitinib alone group (HR, 0.58; 95% CI, 0.46-0.73; P <.001).
The phase 3 FLAURA 2 trial (NCT04035486) will investigate the combination of osimertinib with cisplatin/carboplatin and pemetrexed, followed by maintenance therapy with osimertinib/pemetrexed vs osimertinib in patients with EGFR-mutated locally advanced or metastatic nonsquamous NSCLC. Piotrowska is eagerly anticipating those results but said getting patients to commit to office visits for IV treatment when they could simply receive oral targeted treatment may be difficult.
“I think it begs the question of, can we select the patients that really need that addition of chemotherapy?” she said.
Piotrowska said it will be key to identify the patients at the greatest risk for progression while on osimertinib. She called the phase 2 SHEDDER (NCT04410796) one of the most exciting trials exploring frontline treatment. Patients with metastatic EGFR-mutant NSCLC will receive first-line osimertinib therapy. Participants with persistent ctDNA detected in plasma samples will then be randomly assigned to osimertinib alone or with chemotherapy.
“We have prior data from other studies that have shown that those patients tend to do well, so they just stay on osimertinib, but it’s the patients who haven’t cleared their ctDNA where we know that there’s a higher risk of early relapse who are being randomized to osimertinib versus osimertinib plus chemotherapy,” she said. “I think this may be a positive study and I think it would give us credence to say to a patient, ‘You’re on osimertinib, but you have a high risk factor, you’re not clearing your ctDNA,’ and that may be more rationale for maybe then committing that patient to adding chemotherapy.”