The combination of the third-generation EGFR-TKI aumolertinib and platinum-based chemotherapy compared with aumolertinib monotherapy improves profession-free survival in patients with EGFR-mutant advanced NSCLC.

An open-label phase 3 RCT, published in The Lancet Oncology [link here], said aumolertinib monotherapy is already approved in China and the UK for patients with locally advanced or metastatic NSCLC and activating EGFR mutations.

However the effectiveness of these EGFR-TKIs was often limited by the emergence of drug resistance and subsequent disease progression, leading to the need for other treatment options.

The Chinese study enrolled 624 patients from 60 hospitals with locally advanced or metastatic EGFR-mutant advanced NSCLC, favourable ECOG performance status of 0-1, and an estimated survival time of at least 12 weeks.

The median age of patients was 59 years, 54% were female, and most (71%) were never smokers. CNS metastases were present in 30% and liver metastases in 13% of patients.

The study found progression or death occurred in 36% patients in the combination treatment group versus 57% in the monotherapy group.

The median progression-free survival assessed by BICR was significantly improved at 28·9 months in the combination group versus 18·9 months in the monotherapy group (HR 0·47, 95% CI 0·37–0·60; log-rank p<0·0001).

The PFS benefit of combination therapy was consistent across all subgroups including age, sex, smoking status, EGFR mutation type, presence of brain metastases, and baseline ECOG performance status.

In other findings:

• The objective response rate was 93·2% in the combination group and 87·3% in the monotherapy group (OR 2·03, 95% CI 1·16 to 3·55)
• The disease control rate was 96·5% and 96·5% respectively
• The median duration of response was 27·6 months versus 19·3 months
• The median depth of response was −62·2% versus −57·9%.

“The combination of an EGFR-TKI with chemotherapy appears to offer synergistic benefits by precisely targeting EGFR-dependent cells while concurrently eliminating resistant clones, thereby significantly improving progression-free survival,” it said.

“A key clinical challenge remains optimal patient selection for combination therapy. ctDNA guided adaptive therapy can guide treatment intensification, or treatment de-escalation.”

Safety profile 

Regarding safety, the most common adverse events of any grade in the combination group were haematological toxicities, “…primarily due to known chemotherapy-related toxicities”.

Serious adverse events occurred in 36% patients in the combination group and in 17% in the monotherapy group.

Adverse events led to dose interruptions in 64% in the combination group and 25% in the monotherapy group, dose reductions in 44% versus 3%, and treatment discontinuations in 21% versus 2%.

Other common adverse events previously reported with aumolertinib such as blood creatine phosphokinase increases (56% vs 51%) and rash (24% vs 17%) were similar in the two treatment groups and mostly grade 1 or 2 in severity.

Treatment-related deaths occurred in one patient in the combination group due to encephalopathy and two in the monotherapy group due to a pulmonary embolism and respiratory failure with circulatory collapse.

“The high chemotherapy completion rate of the planned treatment regimen (89%) underscores that although the frequency of adverse events was higher, these events were clinically manageable and reversible through the predefined protocol-specified measures,” it said.

“These findings support the idea that the combination of aumolertinib and platinum-based chemotherapy could serve as a new effective first-line treatment option for patients with EGFR-sensitive mutated NSCLC. Overall survival data require further follow-up to confirm long-term clinical benefit,” they concluded.

The study was funded in part by the Jiangsu Hansoh Pharmaceutical Group.