Exploring New Therapeutic Options in ALK-Rearranged Lung Cancer

There is a growing potential for more treatment options to address the heterogeneity of mechanism of resistance for patients with ALK-rearranged non—small cell lung cancer (NSCLC), says Leena Gandhi, M.D., Ph.D.

“Things change so fast that now approval within four years of discovery or approval within three years for a novel drug is sort of our standard now for TKIs and targeted therapies,” Gandhi, a medical oncologist at the Perlmutter Cancer Center at NYU Langone School of Medicine, said in a presentation during the 11^th Annual New York Lung Cancer Symposium.

Xalkori (crizotinib) was approved by the FDA in 2011 as a treatment with ALK-rearranged patients with NSCLC. It quickly became the standard of care. In the past five years, however, researchers continued to investigate new agents.

“With the approval of alectinib (Alecensa), the paradigm of crizotinib as first-line treatment followed by ceritinib (Zykadia), which was a quite short-lived paradigm, I think, has changed— not necessarily based on efficacy differences, which were not clearly that different, and not even necessarily based on CNS efficacy differences. Really, it is based on toxicity differences,” said Gandhi.

Second-line Zykadia is associated with significant levels of gastrointestinal toxicities for many patients, which led to the rise of the use of second-line Alecensa after frontline Xalkori, Gandhi added.

Further research has also led to the questioning of Xalkori as the optimal first-line treatment. In a 2013 study published in Lancet Oncology, there was a 93.5 percent response rate in Xalkori -naïve Japanese patients, with a median progression-free survival (PFS) longer than three years. Gandhi also cited the ASCEND trials, which suggested a frontline PFS of 16 to 18 months with Zykadia. Xalkori followed by Zykadia was associated with a median 17-month PFS, and Xalkori followed by alectinib had an 18-month median PFS.

The J-ALEX trial tested Alecensa versus Xalkori in the frontline for ALK-rearranged NSCLC and found that patients on Alecensa (103 patients) had an 85.4 percent overall response rate, compared with the Xalkori arm (104 patients), which had a 70.2 percent ORR.

“Data just from approval studies of alectinib demonstrated that there are these really quite striking complete response rates, even in previously radiated patients that — although we've seen some complete responses in many of the next-generation inhibitors — we haven’t seen that kind of activity,” Gandhi said. “Whether that's truly different — without a drug comparison we don’t know — but it's certainly suggestive that it may be in that setting.”

However, there are still many questions surrounding these drugs as next-generation inhibitors, such as brigatinib and lorlatinib, are being investigated in ALK-rearranged NSCLC. Each of these inhibitors having varying efficacy levels against different ALK mutations and have increased potency compared with Xalkori.

“Brigatinib, which was sort of in parallel of being developed at the same time as ceritinib and alectinib, got slowed down a little bit by the fact that there was a dose-dependent serious toxicity seen at relatively high rates. It was really smart to go back and re-evaluate that,” Gandhi said. “Going back and doing a much larger trial comparing either a lower dose or 90 mg for seven days followed by 180 mg continuous dosing demonstrated that you can get very robust responses at that higher dose and minimize the rate of grade 3/4 toxicity.”

If approved, lorlatinib may be an optimal choice as a last-line therapy, because it can have activity after multiple ALK inhibitors.

Serial biopsies and/or liquid biopsies will bring about tailored therapy that will allow oncologists to choose from the large pool of agents available to treat ALK-positive NSCLC, Gandhi said.

“To summarize, ALK is a really different field than EGFR because of the number of drugs we have, the number of potential opportunities we have for treatment and the durability of response for every one of these,” Gandhi said.