Osimertinib plus chemotherapy improves progression-free survival by 18.4 months in TP53 and EGFR-mutated NSCLCAdding chemotherapy to osimertinib extends survival for specific lung cancer

This Phase 3 randomized clinical trial evaluated the efficacy and safety of osimertinib plus chemotherapy compared to osimertinib monotherapy in a specific subset of patients with non-small cell lung cancer (NSCLC). The study enrolled 294 treatment-naive patients with stage IV or recurrent nonsquamous NSCLC who harbored both concurrent TP53 and EGFR-sensitizing mutations. The trial was conducted at a multicenter setting across 17 sites in China.

The intervention group received osimertinib plus chemotherapy, which consisted of pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by a maintenance phase of osimertinib plus pemetrexed. The comparator group received osimertinib monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS).

Results for the primary outcome showed a significant improvement in progression-free survival for the combination group. The median PFS was 34.0 months for the osimertinib plus chemotherapy group compared to 15.6 months for the osimertinum monotherapy group (n=146 in the combination group; n=148 in the monotherapy group). The calculated difference was 18.4 months, with a hazard ratio of 0.44 (95% CI, 9.9-22.3; P <.001).

Secondary outcomes included overall survival, response, safety, and quality of life. While a trend was observed for overall survival, the data remained immature at the time of analysis, with only 30.6% maturity. Regarding safety, the combination group showed a higher incidence of grade 3 or higher treatment-related adverse events compared to the monotherapy group. However, no new safety signals were identified, and specific rates for serious adverse events or treatment discontinuations were not reported.

These findings provide a specific clinical rationale for the management of patients with EGFR-mutated NSCLC who also harbor concurrent TP53 mutations. While the addition of chemotherapy to TKI therapy is a known strategy in NSCLC, this trial specifically highlights the potential benefit in the presence of the TP53 mutation. The high certainty of the progression-free survival data is supported by the Phase 3 randomized design, whereas the certainty for overall survival is lower due to the immature data.

Methodological limitations include the immature overall survival data and the specific geographic focus of the trial. Furthermore, while the combination therapy showed a significant increase in progression-free survival, the safety profile was characterized by a higher incidence of high-grade adverse events in the combination arm. Clinical decisions for patients with this specific mutation profile may now consider the addition of chemotherapy to osimertinib to potentially extend progression-free survival. Questions remain regarding the long-term impact on overall survival and the specific impact on patient quality of life over extended periods.