Two New Drugs for EGFR+ Lung Cancer That Has Progressed

Zosia Chustecka

April 29, 2015

Two new drugs for a specific lung cancer scenario are approaching the market –-- AZD9291 (AstraZeneca Pharmaceuticals LP) and rociletinib (Clovis Oncology), and both companies are preparing to file for approval.

Both drugs are third-generation EGFR inhibitors destined for use in patients who have non–small cell lung cancer (NSCLC) that is EGFR-mutation-positive and has responded to treatment with first-line EGFR inhibitors, but is now progressing.

In about 60% of these cases, the disease is progressing because the tumor has developed a new mutation, known as EGFR T790M. This mutation confers resistance to treatment with first- generation EGFR inhibitors, such as erlotinib (Tarceva, Osi Pharmaceuticals, Inc) and gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) or the second-generation EGFR inhibitor afatinib (Gilotrif, Boehringer Ingelheim Pharmaceuticals, Inc).

When the disease progresses, as it invariably does after about 10 to 12 months in patients receiving EGFR inhibitors, it has not been clear what treatment to offer next, commented Pasi Jänne, MD, PhD, director of the Lower Center for Thoracic Oncology at the Dana-Farber Cancer Institute, Boston, Massachusetts.

"We now have a good treatment strategy for these patients," he told Medscape Medical News.

Dr Jänne is the principal investigator on a clinical trial with AZD9291 published in this week's New England Journal of Medicine. The results of a clinical trial with rociletinib are published in the same issue, from a team led by Lecia Sequist, MD, from Massachusetts General Hospital.

Both drugs appear to have similar efficacy, Dr Jänne commented. Results in the subgroup of patients who are progressing and who have been identified as having the T790M mutation show that for both drugs, response rates are around 60%, and median progression-free survival is around 10 months.

But there are important differences between the two drugs, he added. AZD9291 is taken once daily orally, whereas rociletinib is taken twice daily, and rociletinib has a side effect of hyperglycemia that is not seen with AZD9291.

Dr Sequist and colleagues report that in their clinical trial, hyperglycemia was noted as the most common grade 3 toxic effect (occurring in 47% of 92 patients), but it was successfully managed with dose reduction, oral medication (usually metformin), or both, they wrote.

Better Tolerated

These third-generation EGFR inhibitors are much better tolerated than the earlier EGFR inhibitors, Dr Jänne noted, because they are more specific for mutated vs wild-type EGFR than the earlier drugs. In particular, there is less skin toxicity and diarrhea than is seen with the earlier drugs.

Skin toxicity is seen with all of the earlier EGFR inhibitors and can manifest as an acnelike rash, but it can also lead to dry skin that cracks at the fingertips, leading to infections of the nail bed, he explained.

"We see very little of that with AZD9291," Dr Jänne said. "We start to see a bit of it with the higher doses, but not with the 80-mg once-daily dose that has been selected for future use."

The diarrhea seen with the earlier EGFR inhibitors can result in patients having to take antidiarrheal medication, particularly with afatinib and sometimes with erlotinib, and again, this has not been the case with AZD9291, he said.

The patients taking part in the AZD9291 clinical trial acted as their own controls, inasmuch as they had all previously taken a first- or second-generation EGFR inhibitor. When asked how they compared their experience of taking AZD9291 with that of their taking the earlier EGFR inhibitors, patients said "it was night and day different.... They felt so much better on the new drug and felt closer to their precancer baseline," Dr Jänne commented.

For Patients With T790M Mutation

AZD9291 was recently designated as a fast-track drug by the US Food and Drug Administration, and Dr Jänne predicts that it will be approved before the end of the year. He also anticipates that the labeling will specify that it is for use in patients who have been identified as having developed T790M after experiencing disease progression with EGFR-inhibitor therapy.

"Unfortunately, resistance to first-line EGFR inhibitors happens virtually in everybody, and in the majority of cases (60%), this is mediated by the T790M mutation.... We now have a specific treatment option for these patients, but what this means clinically is for patients who are progressing, we need to test them for this new mutation," he said.

At present, this means having them undergo a tumor biopsy, he said, although in the future, it may be possible to get this information from circulating tumor DNA in the blood or urine, as recently reported by Medscape Medical News.

"If a patient who is progressing has the T790M mutation, then this new class of third-generation EGFR inhibitors makes absolute sense," he said.

At the moment, patients with NSCLC that is EGFR positive (about 10% to 15% of all NSCL among Western patients, and 30% to 35% of Asian patients) are treated up front with a first- or second-generation EGFR inhibitor, which gives them about 1 disease-free year on oral therapy. When they progress, if they have the T790M mutation, the clinical data show that a third-generation EGFR inhibitor will give them about another year disease free on oral therapy, after which, when they progress, they can then move on to chemotherapy or another option. "So we are extending the time to twice as long, and we ultimately hope that this will lead to a prolongation of survival," Dr Jänne said.

"But if patients don't have this mutation, then it becomes less clear as to what the best treatment option is," he said.

It may be that the patients without the T790M mutation would do better to go onto chemotherapy at this point, or perhaps immunotherapy, or perhaps an experimental combination, such as afatinib with cetuximab (Erbitux, Genentech, Inc), an anti-EGFR monoclonal antibody used in the treatment of colorectal cancer. "This is an area of ongoing investigation," he said.

It is also not clear whether there would be benefit from using a third-generation EGFR inhibitor up front as a first-line therapy, he added. This is also being tested in clinical trials.

In an editorial that accompanies the publication of the clinical trials, Ramaswamy Govindan, MD, from Washington University School of Medicine, in St. Louis, Misouri, comments that the studies "underscore the importance of repeating biopsies with molecular analysis at the time of disease progression in patients with EGFR-mutated NSCLC."

Finding a T790M mutation in such a repeat biopsy now has practical relevance, he writes: "In the immediate future, before these drugs are approved and widely available, these patients should be considered for ongoing clinical trials with T790M-specific EGFR tyrosine kinase inhibitors."

Both studies were supported by the manufacturer -- AZD9291 by AstraZeneca, and rociletinib by Clovis. Dr Jänne reports receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceuticals, Pfizer, Merrimack Pharmaceuticals, and Clovis Oncology; receiving lecture fees from Roche; and owning stock in Gatekeeper Pharmaceuticals. Dr Govindan reports consulting for Pfizer, Merck, Boehringer Ingelheim, Clovis Oncology, Helsinn Healthcare, Genentech, AbbVie, and GlaxoSmithKline.

N Engl J Med. 2015;372:1689-99, 1700-1709, 1760-1761.

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