New Drugs Aim to Defeat Tumor Resistance to EGFR Inhibitors


In recent years, many people with non-small cell lung cancer (NSCLC) have been successfully treated with drugs called EGFR inhibitors. But over time, most patients develop resistance, and the drugs stop working. Researchers are hard at work developing new drugs to help patients who can no longer be treated with EGFR inhibitors.

EGFR inhibitors get their name from a gene called EGFR. Many lung cancer tumors have mutations in this gene. These mutations convert EGFR from a normal gene into a cancer gene that initiates and promotes cancer growth. Approximately 10% to 15% of white and 30% to 35% of Asian patients with NSCLC have EGFR mutations.

Drugs targeting mutant EGFR have been developed with the hope that blocking its activation will stop, or at least slow down, the growth of tumors. These efforts have been successful—so much so that drugs like erlotinib (Tarceva) have been approved by government health agencies as first-line treatment for EGFR-mutant, metastatic lung cancer. This means that, rather than using chemotherapy for patients whose tumors have EGFR mutations, an oncologist will most likely prescribe Tarceva.

Most patients respond to Tarceva, their tumors shrinking or even becoming undetectable. However, this effect is temporary. Most tumors come back, and most of them are ‘equipped’ with a new mutation in EGFR, known as T790M. T790M develops in response to Tarceva and makes the now double-mutant EGFR protein invincible to this drug. EGFR T790M continues to ‘drive’ tumor growth and metastases in spite of a patient taking oral Tarceva.

Biotech and pharma companies are now developing drugs that could inhibit EGFR-T790M. Recent progress reports suggest that this effort is starting to achieve its goal. One of the more advanced drugs is rociletinib (CO-1686), from Clovis Oncology. In 2014, rociletinib received a ‘breakthrough therapy’ designation from the U.S. Food and Drug Administration (FDA). This means that review and approval will be accelerated so that rociletinib can more quickly reach patients in the U.S., outside of clinical trials.

The breakthrough therapy designation was based on results from a phase I/II clinical trial. The trial enrolled 62 patients (22 with a confirmed T790M mutation) who had already received and failed an average of three different lines of treatment, including two EGFR-targeted drugs like Tarceva. After treatment with rociletinib, tumors shrank or became undetectable in 64% of the patients. Accounting for patients whose disease stabilized, a total of 91% had a clinical benefit. The most common side effect was elevation of blood sugar, but this could be controlled with drugs like metformin or insulin. Patients with T790M mutations experienced a median of over 10 months without their cancer worsening—a clear success for a group of patients with no other treatment options.

Clovis is currently sponsoring four clinical trials with rociletinib: one is for patients who already had treatment with Tarceva or other EGFR inhibitors (gefitinib, dacomitinib, or afatinib), and developed the T790M mutation (NCT02147990). One large, phase III trial, NCT02322281 (enrollment starting soon), will compare rociletinib to chemotherapy in patients who have also developed resistance to EGFR inhibitors. (This trial is randomized, meaning the patients will not get to choose whether they receive rociletinib or a standard treatment for comparison.) Two more trials are for patients who have EGFR mutations, but have not yet been treated with EGFR inhibitors (NCT02186301 and NCT02186301).

Clovis has competition. The competing drug from AstraZeneca, AZD9291, was described at the European Society of Medical Oncology (ESMO) meeting last year. In a clinical trial, tumors shrank or became undetectable in 61% of 127 patients with advanced, T790M-mutated NSCLC. These good responses lasted a median of 8.2 months. AZD9291 is currently being tested in several trials for NSCLC, both as a single agent (NCT02296125) and in combination with other drugs (NCT02143466, NCT02179671).

A third T790M-targeted drug, ASP8273 (from Astellas Pharma), is further behind in development. So far, the only available test results are for a small group of patients. Tumors shrank in seven of nine patients who had both EGFR and T790M mutations. Side effects included diarrhea and nausea. These preliminary results were from a phase I/II trial ongoing in Japan (NCT02192697). A phase I trial in the U.S., NCT02113813, is also recruiting patients.