The epidermal growth factor receptor (EGFR) is dysregulated by a variety of mechanisms in non-small cell lung cancer (NSCLC). Drugs that target EGFR, therefore, have become an integral component of care, although their optimal use is still being refined. Two experts in this area addressed some of the relevant clinical conundrums, at an Education Session held at the 2010 ASCO Annual Meeting.

Tony Mok, MD, Professor of Oncology at the Chinese University of Hong Kong, said randomized studies have established the key driver of response to EGFR-targeted therapy to be the activating EGFR mutations, not Asian ethnicity. In the pivotal Iressa Pan-Asia Study,¹ response rates to gefitinib (Iressa) were 71% for patients with mutations compared to 1% for those without. Perhaps as importantly, Dr. Mok added, the Pan-Asia study showed that for treatment-naive patients, chemotherapy is superior to a tyrosine kinase inhibitor (TKI) in the absence of EGFR mutations.

"This study informed us that we have to select patients for their biomarkers before putting them on an EGFR TKI in the first-line setting," he noted.

Emerging data would suggest that the exon 19 deletion may be more predictive of response to EGFR TKIs than exon 21 mutation, as this group has better response rates and progression-free survival (PFS),^2,3 although a recent study found no differences.⁴ Zeroing in on the mutations would help define candidates for anti-EGFR treatments.

The Japanese NEJGSG002 study,⁵ the WJTOG3405 study,⁴ and the Spanish Lung Cancer Group trial³ confirmed the benefits of TKIs in patients with EGFR mutations, but no large comparative study has established the superiority of one agent over the other, he added. A recent pooled analysis of 1,809 patients, however, found median PFS to be 13.2 months with erlotinib (Tarceva) and 9.8 months with gefitinib (5.9 months with chemotherapy),⁶ offering a "suggestion" of enhanced benefit with erlotinib, but further studies are needed, according to Dr. Mok.

Treating Beyond Progression

Research is focusing on better understanding mechanisms of resistance to TKIs and strategies to overcome them, said David M. Jackman, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

Dr. Jackman noted that when TKIs are stopped, patients could have worsening of disease. Therefore, progression should be measured while the patient is on treatment. "We don't want to misinterpret radiologic worsening as tumor progression related to resistance. It might just be, for example, because the drug was held for treatment of a rash," he pointed out.

Similarly, progression in the central nervous system may not represent a genetic change associated with resistance, but rather, insufficient penetration of drug into a sanctuary site. In this case, increasing the dose may achieve the proper concentration. "We have induced cytologic clearance of lung cancer cells from the cerebrospinal fluid using daily high-dose gefitinib for 2 weeks, followed by 2 weeks of maintenance gefitinib," he reported.

Novel means of overcoming resistance are in development, including three irreversible EGFR inhibitors: PF299804, BIBW2992, and HKI-272. Other potential approaches are to combine a TKI with cetuximab (Erbitux), a strategy that reduced tumor burden in a study presented at the 2010 ASCO Annual Meeting.⁷ TKIs might also be combined with inhibitors of PI3 kinase, mTOR, heat shock protein 90, or c-MET. Amplification of c-MET is a key mechanism of resistance, and recent phase II data suggested dual inhibition with erlotinib and the c-MET inhibitor ARQ197 might be effective.⁸

Meanwhile, clinicians should remember that EGFR mutations also predict for response to chemotherapy, "so standard chemotherapy is of value in the second-line setting," Dr. Jackman said. "The larger question is whether to keep the patient on the TKI," he added. "In patients with indolent disease, sometimes continuing the TKI alone can provide long-term benefit. When you remove the TKI, tumors threaten to flare. My bias is to keep the TKI and give chemotherapy on top of this, rather than make a wholesale switch."

Sloan-Kettering Genotyping All Lung Adenocarcinomas

Clearly, the key to optimally treating NSCLC is to unravel the genetic makeup of the patient's tumor. The Lung Cancer Molecular Analysis Project at Memorial Sloan-Kettering Cancer Center (MSKCC) is seeking to do just that by routinely testing all NSCLC specimens for mutations in EGFR and KRAS, which are the most common, along with 40 additional abnormalities in seven genes.

EGFR mutations are found in approximately 19% to 26% of adenocarcinomas, making them highly sensitive to EGFR inhibitors. About 23% to 30% of tumors have KRAS mutations, which appear to be associated with treatment resistance.

MSKCC oncologists use the test results to select patients for treatment with erlotinib or gefitinib and to identify patients' eligibility for biomarker-driven clinical trials, said Mark Kris, MD, Chief of the Thoracic Oncology Service at MSKCC, at a poster presentation at the Annual Meeting.⁹ Table 1 shows the frequency of various mutations revealed in data on 541 tumors assessed by the lung cancer molecular analysis project (Table 1).

"The [lung cancer-molecular analysis] program has permitted molecular testing in 96% of patients with available tissue. We detected a driver mutation in 6%, and the program guided the selection of therapy in 18% of patients with EGFR, KRAS, and EML4-ALK mutations. The [lung cancer-molecular analysis project] findings support making upfront genotyping of lung adenocarcinomas part of routine care," Dr. Kris said.

Protocols for agents targeting BRAF, MEK1, HER2, and PIK3CA are in the approval process, and the investigators will collaborate with Lung Cancer Mutation Consortium institutions to complete trials of agents targeting these mutations.

Elsewhere, Oncologists Slow to Order Molecular Tests

While NSCLC patients at MSKCC are tested for an array of molecular alterations, the average American oncologist takes the opposite approach. According to a survey conducted by Xcenda, LLC, a full-service consultancy, market research, and managed markets agency in the healthcare space, 62% of American medical oncologists would not order molecular testing before treating a hypothetical stage IV NSCLC patient.¹⁰

"Only a minority of consultants planned to order specific testing to assess possible chemosensitivity (ERCC-1) or KRAS or EGFR status," said Mark R. Green, MD, Chief Medical Officer of Xcenda, Palm Harbor, Florida, at another poster presentation at the Annual Meeting.

He and his colleagues queried 585 oncologists as to how they incorporate marker testing in their treatment planning for a hypothetical 58-year-old female, former smoker presenting with stage IV lung adenocarcinoma. Three-quarters of respondents were in community practice and one-quarter practiced in academic centers or teaching hospitals. About half had practiced for at least 11 years and saw at least one new NSCLC patient per week.

Participants were asked whether they would request special marker studies on the tissue before finalizing their management plans, and were presented with 10 testing options.

Prior to treating, 60% of oncologists would order no molecular tests, including 64% of those in community practice and 51% in academic settings (Fig. 1). For those who would test, the single most common choice was for EGFR status, which was selected by just 10% of respondents; 9% would order at least two of the following: EGFR, KRAS, or ERCC-1. No clear correlation was seen between time out of training or volume of lung cancer patients and plans for more frequent testing.

"The notion here, among nearly 600 medical oncologists, is 'I am not persuaded by the discussion, the data, and the analyses [in support of testing] that the clinical impact is enough to consider these tests mandatory for optimum treatment,'" Dr. Green told The ASCO Post.

While he proposed a number of reasons for their reluctance, he said, "The bottom line is that from March through September 2009, the majority of oncologists, who had substantial lung cancer experience, were not planning to use molecular studies as a basis for finalizing their management plans."

It should be noted that most respondents were surveyed prior to the publication of two high-profile studies1,3 and a relevant editorial in The New England Journal of Medicine.¹¹ Dr. Green acknowledged that if surveyed today, some oncologists might answer differently. Indeed, over time there was an increase in the proportion of physicians who would order at least one test, from 28% initially to 46% by mid-September 2009.

Commenting on the findings, Dr. Kris suggested, "There is a widely held but unsubstantiated belief that erlotinib is helpful, regardless of mutation status. Many physicians are giving erlotinib, especially second-line, without testing. But the data are incontrovertible that any benefit is trivial in unselected patients. Plus, the maintenance benefit of chemotherapy is twice that of erlotinib, and from the [Pan-Asia] study we know that a TKI may actually be detrimental in wild-type patients. You need to test these patients, and as time goes on I think more doctors will realize this."

Xcenda is continuing to survey oncologists on this and related issues in order to create "a matrix of information" that will guide the personalization of NSCLC care, Dr. Green said. ■

References

1. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009.
2. Fukuoka M, Wu Y, Thongprasert S, et al: Biomarker analyses from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia. 2010 ASCO Annual Meeting. Abstract 8006. Presented May 31, 2010.
3. Rosell R, Moran T, Queralt C, et al: Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958-967, 2009.
4. Mitsudomi T, Morita S, Yatabe Y, et al: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomized phase 3 trial. Lancet Oncol 11:121-128, 2010.
5. Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or Chemotherapy for Non-Small-Cell Lung Cancer with Mutated EGFR. N Engl J Med 362:2380-2388, 2010.
6. Paz-Ares L, Soulières D, Melezinek I, et al: Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: Pooled analysis. J Cell Mol Med 14:51-69, 2010.
7. Riely GJ, Janjigian YY, Azzoli CG, et al: Phase II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. 2010 ASCO Annual Meeting. Abstract 7557. Presented June 6, 2010.
8. Schiller JH, Akerley WL, Brugger W, et al: Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer. 2010 ASCO Annual Meeting. Abstract LBA7502. Presented June 5, 2010.
9. Kris MG, Lau CY, Ang D, et al: Initial results of LC-MAP: An institutional program to routinely profile tumor specimens for the presence of mutations in targetable pathways in all patients with lung adenocarcinoma. 2010 ASCO Annual Meeting. Abstract 7009. Presented June 8, 2010.
10. Green MR, Wozniak AJ, Willey J, et al: Plans of American medical oncologists to order molecular testing before starting first-line therapy for patients with stage IV non-small cell lung cancer. 2010 ASCO Annual Meeting. Abstract 7568. Presented June 6, 2010.
11. Gazdar AF: Personalized medicine and inhibition of EGFR signaling in lung cancer. N Engl J Med 361:1018-1020, 2009.