Zosia Chustecka

May 14, 2014

A new EGFR inhibitor appears to overcome resistance in patients with non-small cell lung cancer (NSCLC) who have tested positive for EGFR but have stopped responding to first-line targeted therapy.

At present, there is no standard treatment available for such patients, but early clinical results with the investigational drug AZD9291 (under development by AstraZeneca) suggest that it may fill this niche.

Results with the new drug will be reported at the forthcoming 2014 Annual Meeting of the American Society of Clinical Oncology® (ASCO), and were highlighted today in a premeeting presscast.

Another similar drug, CO-1686, from Clovis, is at a similar stage of development. Both these new drugs have activity against the T790M mutation, which is responsible for the acquired resistance to EGFR inhibitors in about 60% of cases.

The data on AZD9291 come from a phase 1 study conducted in 199 patients with advanced NSCLC harboring EGFR mutations, who had documented radiographical progression after receiving treatment with 1 or more EGFR inhibitors.

This was an international study; 65% of patients were Asian and 32% were white. This is important because EGFR mutations occur more commonly among Asian patients (in around 40% of patients compared with 10% to 15% of white patients, although these estimates vary).

Patients received a range of different doses of AZD9291 (20 mg, 40 mg, 80 mg, 160 mg, 240 mg), and responses were seen at all doses and in all subgroups of patients, including those with brain metastases. Overall, 51% of patients showed tumor shrinkage. The responses are continuing in nearly all patients, with the longest response lasting 8 months, said lead author Pasi Jänne, MD, PhD, professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School in Boston.

The dose chosen for future trials was 80 mg once daily, Dr. Jänne said.

AZD9291 has 2 novelties that distinguish it from the EGFR inhibitors already on the market, which include erlotinib (Tarceva) and afatinib (Giotrif) in the United States, and also gefinitib (Iressa) outside of the United States.

Firstly, the new drug is active against theT790Mmutation, in addition to EGFR mutations. The T790M mutation is thought to be responsible for the development of resistance to EGFR inhibitors in about 60% of patients.

Among the 199 patients taking part in the phase 1 clinical trial, 89 had a confirmed T790M mutation, and 64% of these patients responded to AZD9291.

This population of patients with EGFR-positive NSCLC who have progressed on a first-time EGFR inhibitor and who have an identified T790 mutation is covered by a breakthrough designation granted to the new drug by the US Food and Drug Administration.

This is also the patient population being studied in the ongoing AURA trial (NCT01802632).

Among the remaining patients, 43 patients did not have this T790M mutation, and they showed a much lower response rate of 23%, but the fact that there was some response suggests that the new drug is more potent and has activity over and above the other EGFR inhibitors, Dr. Jänne said. "In addition, some of the patients are likely to be reresponders," he commented; this is a phenomenon also seen with erlotinib and the other drugs, where patients stop responding but then start to respond to the drug once again, he added.

Secondly, AZD9291 appears to be more selective than the currently available agents, in that it inhibits EGFR only in the tumor, and not in the skin and other organs, which can lead to skin rash or acne. This translates to a better toxicity profile, so the typical EGFR inhibitor adverse effects of diarrhea and skin rash are seen "less frequently and are much milder" with AZD9291 than have been seen with the other drugs, commented Peter Yu, MD, president-elect of ASCO, and director of cancer research at the Palo Alto Medical Foundation in Mountain View, California.

"The reduced skin toxicity seen with AZD9291 heralds greater precision in targeting cancer mutations and sparing healthy tissues, which retain normal germ-line EGFR status," Dr. Yu said in a statement.

During the presscast, Dr. Jänne gave some details of the toxicities seen with ADZ9291. There were no dose-limiting toxicities, and the adverse effects seen were "mostly mild in nature." Most common adverse events, mostly grade 1, were diarrhea (30%), rash (24%), and nausea (17%).

Grade 3 or 4 adverse events were seen in 16 patients, 6 patients (3%) had dose reductions, and 7 patients (4%) discontinued because of adverse events. There were 5 reports of interstitial lung disease-like events (1 seen with 80 mg dose and 4 with the 160 mg dose). All patients responded to treatment and recovered fully, Dr. Jänne said. Further review of these events is ongoing.

Approached for comment, Ben Creelan, MD, from the department of thoracic oncology at the Moffitt Cancer Center in Tampa, Florida, said that resistance to EGFR inhibitors is "almost inevitable." Patients on these targeted agents have a great initial response, but they develop resistance and stop responding after a year or 2. "This happens in nearly all patients," he said: out of around 2000 patients treated at their center, he has seen only 1 patient who did not develop resistance, and she has been on gefitinib since 2006, but that is a "very remarkable case, very rare case."

At present, there is no standard therapy for patients who become resistant. "We use palliative chemotherapy," Dr. Creelan commented.

In over half of these cases, the resistance to EGFR inhibitors is due to a new mutation, T790M, and "the beauty of these third generation agents such as AZD9291 and CO-1686 is that they are active against this mutation."

The data on AZD9291 from the phase 1 trial in the ASCO abstract and data on CO-1686 that was presented previously at lung cancer meetings show similar activity for both drugs — responses in about 65% of patients who have the T790M mutation, Dr. Creelan commented.

Looking ahead to the future, Dr. Creelan said that prescribing of these new drugs may be limited in their labeling to patients who are known to have a T790M mutation, but at the moment for this to be confirmed a lung biopsy is needed, and this is not always possible. In addition, it takes time for the tissue to be analyzed. There are tests under development that would allow identification of the mutation from plasma, but these are not available yet; they are maybe 2 years or so away from the clinic.

"I would feel comfortable using these drugs" even in the absence of a biopsy in patients who have become resistant to first-line EGFR inhibitors, Dr. Creelan said. He speculated that in the community, oncologists would use these agents at the time of progression. These third-generation agents are more selective and better tolerated, and he predicts that in the longer term they will be investigated for first-line use and will "give the currently available drug a run for their money."

The study was funded by AstraZeneca. Dr. Jänne reports serving in a consultant or advisory role with Chugai, Sanofi, Merrimack, Pfizer, AstraZeneca, Boehringer Ingelheim, Genentech, and Clovis; and owning stock in Gatekeeper Pharmaceuticals. Several study coauthors are employees of AstraZeneca.

2014 Annual Meeting of the American Society of Clinical Oncology: Abstract 8009. To be presented May 31, 2014.

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