Another Targeted Agent for Therapy-Resistant EGFR-Mutated Lung Cancer

The targeted agent rociletinib (CO-1686, Clovis Oncology, Inc.), has shown promising activity in non-small cell lung cancer (NSCLC) patients who have become resistant to current available therapies. Results of the phase I/II clinical trial were published in TheNew England Journal of Medicine,¹ and partial results from the trial were previously presented at the American Society of Clinical Oncology annual meeting in 2014.

Patients with EGFR-mutated lung cancer represent about 10% to 15% of patients in the US and Europe, and about 30% to 35% of Asian patients. The vast majority of these patients has either an exon 19 or exon 21 EGFR mutations at the time of diagnosis, and generally responds to currently available EGFR tyrosine kinase inhibitors including gefitinib (Iressa), erlotinib (Tarceva) and afatinib (Gilotrif). Objective responses range from about 50% to 70% in treatment naive NSCLC patients. Yet, new approaches are needed as these EGFR-mutant NSCLC patients generally develop resistance within one year of starting anti-EGFR therapy.

Rociletinib is a small molecule, oral mutation-selective inhibitor of EGFR that targets EGFR exon deletions, and the L858R and T790M mutations, but not wild-type EGFR. T790M is so far the most commonly found resistance mutation to first and second generation EGFR inhibitors, found in about 50% to 60% of EGFR-mutated NSCLC patients following targeted therapy.  Median survival is estimated to be less than 2 years after the T790M mutation emerges, as there are no available targeted agents specifically for this mutation.

Patients enrolled in the trial had all had received at least one previous EGFR tyrosine kinase inhibitor. Patients had received a median of four prior lines of therapy and 50% (65 of 130 patients) had three or more sites of metastases. Forty-four percent of the patients had a history of brain metastases.

In the phase I dose escalation portion of the trial, the maximum tolerated dose was not reached and the maximum dose tested was 900 mg, twice daily.

The phase II portion of the trial tested twice daily, 500 mg, 625 mg, and 750 mg doses.

Of the 148 patients in the phase II portion of the trial who could be tested for the T790M mutation, 78 (53%) tested positive. Among all T790M-positive patients treated at any dose, the objective response rate was 59% (27 of 46 patients)--all of whom had a partial response. An additional 16 patients had stable disease, resulting in a disease control rate of 93%. Among the T790M-negative patients, the response rate was 29% and the disease control rate was 59%. Three of 20 patients whose tumors could not be assessed for the presence of the T790M mutation responded to therapy.

The median follow up was 10.5 weeks.

Response rates were similar between patients with either a deletion 19 or L858R-EGFR mutation. The estimated median progression-free survival was 13.1 months with 82% of the patients still censored at the time of analysis.

Rociletinib was generally well-tolerated according to the study authors. The most frequent grade 3 adverse event, occurring in 20 of 92 patients treated (22%), was hyperglycemia, which was managed with dose reductions and metformin (Glucophage), and did not result in drug discontinuation. Thirty-five (38%) of the 92 patients received metformin or another glucose-lowering therapy for hyperglycemia. Other common adverse events included nausea, fatigue, diarrhea, and decreased appetite. Grade 3 prolongation of the QT interval occurred in five patients, which resulted in no symptoms and was managed with dose reductions.

"Our finding that rociletinib is an active treatment for EGFR-mutant tumors that have developed T790M-driven resistance is a great leap forward for patients because until now, we have not had an effective personalized therapy for them," said study author Lecia V. Sequist, MD, MPH, of the Massachusetts General Hospital Cancer Center and principal investigator of the study in a statement.

While resistance to rociletinib can develop, according to Dr. Sequist, the drug does not target the wild-type EGFR protein, which makes this targeted therapy a better candidate for combination with other therapies, which could attenuate the development of resistance.

Other agents, including AZD9291, are also in development for resistant EGFR-mutated NSCLC, particularly those patients whose tumors harbor the T790M resistance mutation.

This Clovis Oncology study  with rociletinib is still currently enrolling patients.

References:

• Sequist LV, Soria JC, Goldman JW, et al. (2015). Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer. The New England Journal of Medicine.