Approximately 10% to 15% of patients with advanced non–small cell lung (NSCLC) cancer have mutations in the epidermal growth factor receptor (EGFR) in tumor cells. Specific therapies to inhibit the activity of EGFR-mutated NSCLC have now been clearly shown to improve response rate and progression-free survival compared with cytotoxic chemotherapy in this subset of patients. There is some evidence to suggest that even overall survival might be improved with upfront use of afatinib (Gilotrif, vs platinum-based doublet chemotherapy) in ­EGFR-mutated NSCLC involving exon 19 deletions. However, nearly all patients with EGFR-mutated NSCLC eventually develop progressive disease and succumb to widespread metastatic disease.

Nearly 50% of patients with EGFR-mutated NSCLC have the gatekeeper mutation in which threonine is replaced with methionine (T790M), resulting in decreased affinity for the first-generation inhibitors. Unfortunately, cytotoxic chemotherapy drugs and second-generation EGFR tyrosine kinase inhibitors, such as neratinib, afatinib, and dacomitinib, are not very active in this setting.

Novel Agents Offer New Hope

Two papers recently published in The New England Journal of Medicine and reviewed in this issue of The ASCO Post have given new hope for patients with the EGFR T790M mutation.

Jänne and colleagues¹ conducted a phase I study with an expansion cohort for the T790M population with the EGFR inhibitor AZD9291. A total of 253 patients were treated, including 222 patients in 5 extension cohorts.

The overall objective tumor response rate was 51% (95% confidence interval [CI] = 45%–58%). Among 127 patients with centrally confirmed EGFR T790M, the response rate was 61% (95% CI = 52%–70%). The response rate among 61 patients without centrally detectable EGFR T790M was only 21% (95% CI = 12%–34%). Median progression-free survival was longer in the T790M-positive patients (9.6 months, 95% CI = 8.3 months to not reached) than in those without T790M (2.8 months, 95% CI = 2.1–4.3 months).

Most notably, AZD9291 was extremely well tolerated. Since AZD9291 is specific for the mutated EGFR, the typical side effects related to the inhibition of wild-type EGFR were seen less frequently. The most common adverse events (all grades) were diarrhea, rash, nausea, and decreased appetite.

Rociletinib (CO-1686) is active against EGFR-mutated NSCLC with or without T790M mutation. In the phase I/II study reported by Sequist et al,² rociletinib was administered to 130 patients with EGFR-mutated NSCLC who had disease progression following treatment with an EGFR inhibitor. In the expansion cohort, patients with EGFR T790M-positive disease received rociletinib at a dose of 500 mg twice a day to 750 mg twice a day.

The objective response rate among 46 patients with T790M-positive disease who could be evaluated was 59% (95% CI = 45%–73%), and the response rate among the T790M-negative patients was 29% (95% CI = 8%–51%). As was observed with AZD9291, the estimated median progression-free survival was markedly longer in the T790M-positive patients than in the T790M-negative patients (13.1 months, 95% CI = 5.4–13.1 months, vs 5.6 months, 95% CI = 1.3 months to not reached).

Reasonable Future Options

Just like AZD9291, rociletinib was extremely well tolerated, given its selectivity for the mutant form of EGFR. Unlike what was observed with AZD9291, hyperglycemia was observed with rociletinib treatment but was well tolerated and easily managed with oral hypoglycemic drugs.

Clearly, these two drugs, when they are approved, will represent a reasonable option for patients with EGFR-mutated NSCLC with the T790M mutation. It is important to biopsy tumors at the time of disease progression in patients with EGFR-mutated NSCLC, since these agents are available for now as a part of some ongoing trials or through compassionate use programs.

It is important to understand the molecular mechanisms underlying the treatment resistance in patients with EGFR-mutated NSCLC who do not have T790M mutations so that appropriate therapies can be developed in this population. Without question, patients who receive rociletinib or AZD9291 are likely to develop resistance to therapy. Molecular mechanisms underlying treatment resistance to these third-generation EGFR tyrosine kinase inhibitors will need to be studied. Currently, efforts are ongoing to optimize plasma-based screening for the emergence of EGFR T790M clones.

Progress in the area of immune checkpoint inhibitors and the development of novel third-generation EGFR tyrosine kinase inhibitors represents significant hope for patients with ­EGFR-mutated NSCLC. ■

Disclosure: Dr. Govindan reported no potential conflicts of interest.

References

1. Jänne PA, Yang JC, Kim DW, et al: AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372:1689-1699, 2015.

2. Sequist LV, Soria JC, Goldman JW, et al: Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 372:1700-1709, 2015.