Adding ErbB-TKI to KRAS inhibitor may help circumvent lung cancer resistance

Lung cancer

21 Oct 2021

Prof. David Gandara

Combining a pan-ErbB tyrosine kinase inhibitor, afatinib, with the KRAS inhibitor sotorasib appears feasible in treating non-small cell lung cancer (NSCLC) patients with mutated KRAS whose disease had progressed on prior therapies, including KRAS inhibitor monotherapy, a US study suggests.

Interim results from the phase Ib study CodeBreaK 101 provide proof of principle for the rationale of combining HER family inhibitors with KRAS inhibitors, according to the researchers who report a sotorasib/afatinib combination as showing antitumor activity, including a high degree of disease control, in patients previously progressing on sotorasib alone.

The findings, presented at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics, come from a multi-arm master trial evaluating a variety of targeted and non-targeted anticancer agents in combination with sotorasib.

Study investigator Professor David Gandara, director of thoracic oncology at UC Davis Comprehensive Cancer Center, said activation of the ErbB/HER family of epidermal growth factor receptor (EGFR) tyrosine kinases through amplification, mutation, or overexpression has been proposed as a potential resistance mechanism to KRAS inhibition.

“KRAS was considered an undruggable target until recently and the approval of the first direct KRAS G12C inhibitor, sotorasib, by the [FDA] was a crucial milestone for targeted treatment of lung cancer,” he told the meeting.

“Although responses to sotorasib, progression-free survival, and overall survival are higher than observed with prior standard-of-care therapies, combination therapies with sotorasib as a backbone may increase efficacy outcomes and circumvent resistance.”

“As a pan-HER family inhibitor, afatinib is uniquely qualified as a preferred partner to sotorasib and showed the best combination activity in preclinical studies,” added Professor Gandara.

The study enrolled patients with advanced, KRAS p.G12C-mutant NSCLC who had disease progression on prior therapies, including KRAS G12C inhibitors. They were treated with sotorasib and afatinib once per day to evaluate safety, tolerability, and efficacy.

Out of 33 patients, 10 received 960 mg sotorasib and 20 mg afatinib (cohort 1) while 23 received 960 mg sotorasib and 30 mg afatinib (cohort 2). Median treatment duration was 64 days.

According to Professor Gandara, the objective response rate, or the percentage of patients who had a complete response (CR) or partial response (PR), was 20.0% in cohort 1 and 34.% in cohort 2.

Disease control rate, or the total fraction of patients who had CR, PR, or stable disease (SD), was 70.0% and 73.9% in the two cohorts, respectively.

Among five patients who had received prior sotorasib treatment, three had SD, one had progressive disease, and one withdrew from the study due to an adverse event.

Side effects of the combination were consistent with prior reports for each drug individually, and no unexpected toxicities were observed, the study investigators noted. The most common treatment-related adverse events (TRAEs) reported were gastrointestinal (diarrhoea, nausea, and vomiting). Severe TRAEs occurred in 30% of patients within each dose cohort, with diarrhoea being the most common.

Professor Gandara and colleagues say they are interested in further evaluating sotorasib plus afatinib and/or other HER family inhibitors.

“Information on whether combining these agents leads to a different resistance profile than observed with sotorasib monotherapy will be important, and these studies are ongoing,” he said

The study was sponsored and funded by Amgen.

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