With a TP53 co-mutation, adding chemotherapy to osimertinib more than doubled progression-free survival

Design

Multicentre, randomised, open-label, phase 3 trial at 17 sites in China

Population

294 treatment-naive patients with stage IV or recurrent non-squamous non-small-cell lung cancer carrying concurrent EGFR-sensitising and TP53 mutations, median age 57

Primary outcome

Investigator-assessed progression-free survival

Effect

Median 34.0 vs 15.6 months; difference 18.4 months (95 per cent CI 9.9 to 22.3), hazard ratio 0.44 (0.32 to 0.60, P < 0.001); overall survival 30.6 per cent mature

Whether to add chemotherapy to a third-generation EGFR inhibitor in advanced non-small-cell lung cancer has been argued on the basis of trials in unselected EGFR-mutant populations, where the benefit is real but the toxicity cost is paid by everyone. This trial selected for a marker of worse prognosis: 294 treatment-naive patients at 17 Chinese sites with stage IV or recurrent non-squamous disease carrying both an EGFR-sensitising mutation and a concurrent TP53 mutation, randomised to osimertinib plus pemetrexed and carboplatin for four cycles then osimertinib with pemetrexed maintenance, or osimertinib alone.

Median progression-free survival was 34.0 months with the combination against 15.6 months with osimertinib alone - a difference of 18.4 months (95 per cent CI 9.9 to 22.3), hazard ratio 0.44 (0.32 to 0.60, P < 0.001) - at a median follow-up of about 25 months. The benefit held across prespecified subgroups including brain metastases and L858R mutations. Overall survival is 30.6 per cent mature and only trends in favour. Grade 3 or higher treatment-related adverse events were commoner with the combination, with no new safety signal.

The change to practice is to make the co-mutation an actionable question. If a patient's EGFR result comes from a single-gene assay, TP53 status is unknown and this decision cannot be made - which is an argument for next-generation sequencing at diagnosis, the real bottleneck in most Indian centres. Where the result is available and the patient can tolerate platinum doublet, an 18-month difference in progression-free survival is large enough to lead the conversation with, provided the survival data are described honestly as immature.

• Ask whether TP53 status is known; a single-gene EGFR assay cannot answer this question.
• Argue for next-generation sequencing at diagnosis rather than sequential single-gene testing.
• Quote progression-free survival, and say plainly that overall survival data are immature.
• Warn about the higher rate of grade 3 or above adverse events with the combination.
• Note the trial was open-label with investigator-assessed progression, which favours the more visibly active arm.

The statistics, in plain English

A hazard ratio of 0.44 with an interval from 0.32 to 0.60 is a large and precisely estimated effect on progression-free survival. Two cautions attach. Progression-free survival was investigator-assessed in an open-label trial, where knowing the allocation can shift the threshold for calling progression, usually in the active arm's favour. And overall survival at 30.6 per cent maturity is too early to interpret: a progression-free survival gain of this size usually but not always translates, and the honest statement is that it is not yet known.

Read the rest in the app

You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.

Get Daily Doctor — free

Scan to keep reading on your phone. No account needed to start.