The EGF Receptor Continues to be a Promising Target in NSCLC

The epidermal growth factor receptor (EGFR), one of the many receptor tyrosine kinases that are targeted in cancer treatment, is frequently overexpressed or mutated in cancer, which results in cell proliferation, survival, invasion, metastasis, and tumor-induced neoangiogenesis.¹ The approach to targeting this protein in cancer has included the use of small molecule tyrosine kinase inhibitors (TKI) (gefitinib, erlotinib, lapatinib, and afatinib) and monocloncal antibodies (cetuximab, panitumumab, and matuzumab).²

On the second day of the 50th annual meeting of the American Society of Clinical Oncology (ASCO), a session titled, "Targeting EGFR: the next 10 years" provided a progress report on the successful targeting of the protein in non-small cell lung cancer (NSCLC).

The opening talk by Pasi A. Janne, MD, PhD, Dana-Farber Cancer Institute, "Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor—resistant NSCLC," presented results from a phase 1, open-label, multicenter clinical trial with a selective, third generation EGFR-TKI by AstraZeneca, AZD9291, that has been found effective against both EGFR-TKI sensitizing and resistance (T790M) mutations in preclinical models.

The trial, conducted in 199 EGFR mutant (T790M+) NSCLC patients with acquired resistance to EGFR-TKIs, conducted a dose escalation and expansion study of oral AZD9291. Among all the evaluable patients, the confirmed+unconfirmed overall response rate (c+uORR) was 51% (91/177). RECIST responses were observed at all dose levels and in brain metastases. Of 132 patients with centrally confirmed T790M, the c+uORR in 89 EGFR T790M+ patients was 64% (95% CI; 53%, 74%) and in 43 EGFR T790M- patients was 23% (95% CI; 12%, 39%). The overall disease control rate in T790M-positive patients was 96% (85/89). Among the 60 patients with a confirmed response, 97% (58/60) were ongoing at data cut-off and the longest duration of response was >8 months. AZD9291 did not present any dose limiting toxicities, maximum tolerated dose (MTD) was not defined, and the most common adverse events (AEs) were diarrhea, rash, and nausea. Very few grade 3 or higher AEs were observed in any of the cohorts. The overall response rate (ORR) was 53% and the overall disease control rate was 83%. A progression-free survival (PFS) benefit was observed in T790M+ patients. The phase 2 dose has been determined based on this study.

This study showed that T790M+ NSCLC patients with acquired resistance to EGFR-TKIs respond very well to AZD9291 and have a higher ORR compared with the EGFR T790M- patients. Further clinical developments are ongoing, focused on the T790M+ patients.

The subsequent presentation was a dose-finding study for Clovis Oncology’s CO-1686, a molecule that targets the EGFR T790M mutation in NSCLC patients, and which was recently awarded a ‘breakthrough therapy’ designation. Designed to target mutant EGFR, CO-1686 does not bind wild-type EGFR, thus increasing specificity and reducing adverse effects, which makes it eligible as first-line therapy in patients with activating EGFR mutations.³ Clovis wants to develop CO-1686 as an oral treatment for NSCLC patients who have failed EGFR-directed therapy, such as Tarceva (Genentech) or Iressa (AstraZeneca), and have developed the T790M mutation, which is the dominant resistance mechanism to Tarceva/Iressa.³

The results were presented by Lecia V. Sequist, MD, MPH, Massachusetts General Hospital. The first-in-human dose-finding study was conducted in 88 patients with EGFR-mutated advanced NSCLC. The formulation, a hydrogen bromide salt form of CO-1686, was administered to patients who were previously treated with EGFR TKI and had a tumor biopsy in screening for central EGFR genotyping. The patients had previously received a median of 3 therapies 3 (1-7), with 40% having had >1 prior line of EGFR TKI. Related AEs, which were mild and observed in about 10% of patients, included nausea, fatigue, and hyperglycemia (managed with oral hypoglycemic such as metformin and/or dose reduction). A recommended phase 2 dose of 750 mg twice a day was selected.

ORR was 58% in biopsy-proven, heavily pretreated, centrally confirmed T790M+ patients, and the responses deepened over time with longer follow-up. Median PFS is not currently reached, but the current expected estimate is >12 months. CNS responses have been observed.

CO-1686 proves promising in T790M+ EGFR mutant NSCLC patients, and the phase 1 study provided proof-of-concept that targeting the mutant form of EGFR can reduce AEs like diarrhea and rash. The phase 2/3 program initiated this year, called the TIGER (third generation inhibitor of mutant EGFR in lung cancer) program, is actively recruiting patients for 3 registration studies.

The FDA had its representation in this session—Gideon Michael Blumenthal, MD, Holy Cross Hospital, and the clinical team lead with the FDA, presented, "Overall response rate (ORR) as a potential surrogate for progression-free survival (PFS): A meta-analysis of metastatic non-small cell lung cancer (mNSCLC) trials submitted to the FDA." There is an ongoing debate about the appropriate end-points in clinical trials, and they hold immense importance in oncology trials, and the FDA has guidelines for the same.⁴ This ongoing process has been a by-product of the accelerated drug approval process, whereby drug manufacturers often use surrogate endpoints to speed-up drug launch, to save or extend lives. These surrogate endpoints include ORR, PFS, disease-free survival (DFS), time to progression (TTP), and patient-reported outcomes.⁵

Targeted therapies (TT) administered as single agents in molecularly defined mNSCLC subsets are yielding high ORR. Additionally, large improvements in PFS with favorable benefit-risk have served as the basis of drug approval in mNSCLC. However, the relationship between ORR with PFS or OS in mNSCLC is not established. A meta-analysis of 15 mNSCLC trials, which enrolled 12,534 patients, submitted to the FDA was conducted, including 3 trials of TT in molecularly enriched populations with high ORR. The estimated PFS hazard ratio (HR) and OS HR versus the estimated odds ratio (OR) of ORR on the log-scale was calculated.

On a trial level, the meta-analysis of randomized, active-controlled trials indicates a strong correlation between ORR and PFS (R²=0.89), especially for head-to-head trials, which means ORR could be an acceptable surrogate for PFS. A correlation between ORR or PFS and OS is not established and may be confounded by cross-over in the TT trials. This might either be the result of a weak or no relation or a high cross-over, under-power, or long post-program survival, in the 3 small targeted therapy trials in the enriched population, which may confound the analysis. At the trial level, a TT in a molecularly defined subset of mNSCLC with a large magnitude of effect on ORR will likely have a large effect on PFS.

Lawrence H. Schwartz, MD, a diagnostic radiologist at Columbia University Medical Center/New York Presbyterian Hospital, concluded the session with his talk on, "Getting the Right Drug to the Right Patient Faster." Dr Schwartz provided his critic on the current treatment protocols that analyze response versus progression of disease.

“It’s critical to distinguish response and progression as 2 distinct events and should be considered separate,” said Dr Schwartz. Response rate is objective, measurable, and reproducible. Additionally, there’s a 30 plus year history on standardization and measurement of response. But the definition of response needs to be challenged and modified, he said. RR can be strongly correlated with median survival time, but the question remains—– what is “optimal” RR?

Moving on to analyzing progression, Dr Schwartz asked, “How accurate a gold standard is progression?” Alternate methods to assess response and progression to find effective therapies earlier are needed. To this end, the FNIH-VOL PACT simulated studies are being conducted that consider an entire spectrum of metrics, not just RR. “The value proposition of these simulations is that combining metrics with imaging would provide much improved results,” said Dr Schwartz.

He concluded the session by saying that there is a need to combine smarter trials and smarter trials endpoints, including imaging, to derive optimal results/responses.

References

1. Ciardiello 1, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160-1174.

2. Chanprapaph K, Vachiramon V, Rattanakaemakorn P. Epidermal growth factor receptor inhibitors: a review of cutaneous adverse events and management [published online March 2, 104]. Dermatol Res Pract. doi:10.1155/2014/734249.

3. CO-1686. Clovis Oncology website. http://www.clovisoncology.com/products-companion-diagnostics/co-1686/. Accessed May 31, 2014.

4. Guidance for industry clinical trial endpoints for the approval of cancer drugs and biologics. FDA website. http://www.fda.gov/downloads/drugsGuidanceComplianceRegulatoyInformation/Guidance/UCM071590.pdf. Published May 2007. Accessed May 31, 2014.

5. McCain JA. The ongoing evolution of endpoints in oncology. Manag Care. 2010;19(5)(suppl 1). http://www.ptcommunity.com/supplements/1005_CB_endpoints/CB_endpoints.pdf. Accessed May 31, 2014.