Hope for NSCLC Patients with Acquired Resistance to EGFR TKIs

In epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NCSLC), tyrosine kinase inhibitors (TKIs) such as Tarceva® (erlotinib, Genentech/Roche/Astellas) are the standard of care for first-line metastatic patients in the United States and Europe/Japan, respectively.  However, patients receiving TKIs eventually progress, and in approximately 50%-60% of cases, progression is due to development of an additional EGFR mutation called T790M. T790M is termed the “gatekeeper” mutation because none of the approved TKIs for NSCLC patients inhibit the mutation. This represents an unmet need for patients with metastatic NSCLC and is a commercial market opportunity.

Enter third generation EGFR-TKIs, which are all oral, irreversible inhibitors of EGFR that selectively target the mutant protein (including T790M) while leaving the wild-type mostly unmolested. Several such agents, including, AstraZeneca’s AZD9291 (Abstract 8009), Clovis’ CO-1686 (Abstract 8010), and Hanmi’s HM61713 (Abstract 8011), are in early development giving hope to patients with NSCLC who fail first-line EGFR inhibitors. Data from all three of these drugs were presented at this morning’s meeting at the American Society for Clinical Oncology (ASCO).

AZD9291 and CO-1686 both recently received FDA breakthrough status and trials were performed in global populations, with AZD9291 being the largest. HM61713 was studied in a Korean population. All three Phase I trials were performed in well-defined populations with mandatory T790M testing for all patients in the expansion cohorts. The timing of patients’ last TKI was similar across all three trials; however the HM61713 trial had a larger proportion of third-line patients.

In general, all three agents demonstrated impressive efficacy results in the T790M-positive population. The data for AZD9291 and CO-1686 put them ahead of the competition (see table below). In particular, the estimated median progression-free survival (mPFS) of >12 months for CO-1686, if it holds up, as well as the early evidence that it is active against brain metastasis, gives the Clovis compound an edge.  However, the PFS data for both agents are still immature.

Efficacy Data for Third-Generation TKIs in EGFR mutant NSCLC
Sample Size ORR in T790M+ ORR in T790M– mPFS
AZD9291 205 64% 22% NR
CO-1686 72 58% NR NR (est >12 mos)
HM61713 83 29% 12% 4.34 mos

ORR=overall response rate; NR=not reported

Adverse events were generally mild (mostly Grade 1-2) for all three agents, especially in comparison to the high rates of diarrhea (57%) and rash (80%) seen with the first-generation TKI Tarceva. Both AZD9291 and HM61713 treatment resulted in rash characteristic of EGFR wild-type inhibition, while CO-1686 rash levels were nearly absent. Treatment with AZD9291 and HM61713 also resulted in some interstitial lung disease (ILD) or dyspnea. In contrast, CO-1686 had higher rates of hyperglycemia and prolongation of QTc.  Dr. Sequist, who presented the data, was quick to point out that 10% of patients enrolled in the CO-1686 study were diabetic; the discussant, Dr. Lynch, suggested that hyperglycemia management with metformin is well-established and easy to administer but warned that it may have an anticancer effect, which could possibly confound the results in that subgroup. It would be interesting to see the efficacy and safety results in only the non-diabetic patients.

Toxicities AZD9291 (at RP2D of 80mg) CO-1686 HM61713
Diarrhea 20% 23% 21%
Rash 27% 4% 24%
ILD 3% NR 10% (dypsnea)
Hyperglycemia 1% 55% (22%) 0%
QTc prolongation 1% 15% (7%) 3%

It is too early to tell which agent, AZD9291 or CO-1686, will win the race to be first to market in the second-line setting, post-EGFR TKI, EGFR T790M+ space, however, both AstraZeneca and Clovis are charging ahead with additional Phase II and Phase III trials. AstraZeneca’s global Phase II AURA2 trial (NCT02094261) will further test the 80 mg QD dose in patients and the planned confirmatory Phase III AURA3 trial will randomize EGFR TKI-pretreated second-line T790M+ patients against a platinum doublet.

Clovis’ TIGER program includes three trials: TIGER1, a Phase II/III trial in first-line patients (EGFR mutant, not screened for T790M, randomized to receive CO-1686 or Tarceva); TIGER2 (NCT02147990), a Phase II trial that will further test CO-1686 in second-line T790M+ patients; and TIGER3, a Phase III trial that will randomize EGFR TKI-pretreated second-line T790M+ patients against chemotherapy.

The second-line EGFR mutant population is a minor segment of the NSCLC population. In Caucasian NSCLC patients, approximately 15% have an EGFR mutation; thus the T790M acquired resistance population is less than 10% of all NSCLC patients; in Asian patients, this may be up to 20% of the population. Successful penetration of the second-line market will hinge on a change in biomarker testing practices, since it will require (or assume) that physicians confirm a T790M mutation in a post-progression patient. This may not be an easy task to accomplish in practice, since it may require obtaining new biopsy samples or development of less intrusive testing methods (such as circulating DNA).

Both Clovis and AstraZeneca are guiding for submissions in second-line T790M+ patients in 2015, based on their respective Phase I/II trials combined with data from recently initiated AURA2 and TIGER2 trials.  And both companies have confirmatory randomized Phase III trials about to initiate. The race is on!

By Stephanie Hawthorne, Ph.D., Senior Director, and Mara Jeffress, Ph.D., Associate Consultant, Kantar Health

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