Expert Discusses Treatment Advances in ALK-Positive NSCLC

Erminia Massarelli, MD, PhD

The November 2017 FDA approval of the ALK inhibitor alectinib (Alecensa) for the frontline treatment of patients with ALK-positive non—small cell lung cancer (NSCLC) quickly changed the standard of care. But ongoing research suggests that other ALK inhibitors are also poised to significantly impact this patient population.

The FDA granted an accelerated approval to brigatinib (Alunbrig) for treatment of patients with metastatic ALK-positive NSCLC who are resistant to prior crizotinib (Xalkori) in April 2017. The agency then approved brigatinib at a 180-mg dose; previously, it was only available as 30- and 90-mg tablets. Currently, this agent is being investigated as a first-line treatment versus crizotinib in the phase III ATLA-1L trial (NCT02737501).

Also in April 2017, lorlatinib, a selective brain-penetrant ALK/ROS1 tyrosine kinase inhibitor active against most known resistance mutations, won a breakthrough therapy designation for use in patients with ALK-positive metastatic NSCLC who have previously received 1 or more ALK inhibitors. An approval of lorlatinib, experts say, could allow for an appropriate choice for patients who develop resistance to alectinib in the first-line space.

“Brigatinib was approved [as a] second-line ALK inhibitor and that is a very interesting drug. However, lorlatinib is also very promising,” said Erminia Massarelli, MD, PhD.

OncLive: Please provide an overview of your presentation on targeted therapies for ALK-positive NSCLC.

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Massarelli, an associate clinical professor in the Department of Medical Oncology and Therapeutics Research, City of Hope, discussed the evolving paradigm of ALK-positive NSCLC based on recent regulatory decisions and what additional advancements are expected in the year ahead.Massarelli: ALK-mutated NSCLC [makes up a small percentage] of all NSCLCs, and they are presented in a very selected group. They are usually associated with a never smoking history and a young patient population, and are generally diagnosed at metastatic stage. The treatment of [patients with] ALK-translocated lung cancer has been completely changed by our ability [to develop] ALK inhibitors.

How has the FDA approval of alectinib changed this landscape?

The first [ALK inhibitor] was crizotinib (Xalkori). It was readily available in anaplastic large cell lymphoma and approved in 2011 for the first time [in lung cancer]. Naturally, it was shown to be very effective, but now we have new-generation ALK inhibitors. This is mainly alectinib; as shown in the ALEX trial, published by Dr Solange Peters. It shows superiority in comparison to crizotinib in the treatment of first-line ALK-translocated patients.Today, we have a new standard first-line treatment, which is alectinib and is indicated for patients with brain metastases. In fact, in a clinical trial, there was a head-to-head comparison between alectinib and crizotinib. Patients who received alectinib had better progression-free survival than those who got crizotinib. In particular, the development of brain metastases was much lower in the alectinib arm versus the crizotinib arm.

What other inhibitors are showing promise in the pipeline?

In addition, the side effect profile is better for alectinib when compared with crizotinib and ceritinib (Zykadia). Alectinib is a drug easily managed in patients and it allows for patients to have fewer breaks on therapy. We are seeing change in our practice for the first-line setting. Unfortunately, patients eventually develop resistance to ALK inhibitors, even the new-generation inhibitors, and there are many other ALK inhibitors that are being developed. Among those, there are brigatinib and lorlatinib, and they actually have different [levels of] efficacy in different mutations.

Lorlatinib looks like, at least from preclinical data, to have activity in the majority of known ALK mutations. We are waiting on more [data on] this third-generation ALK inhibitor. As of today, we know that first-line alectinib is effective and then next-generation ALK inhibitors are the ones that are promising as second- and third-line therapies. In addition, it is possible to use crizotinib and ceritinib (Zykadia) later on if you have the choice of these drugs.

Since alectinib has had such an impact for ALK-positive patients, do you envision either brigatinib or lorlatinib to have a similar effect on the landscape?

What should community oncologists be most aware of regarding ALK-positive NSCLC?

Across all patient populations, what do you believe to be the biggest advancement in NSCLC?

It is always good to biopsy patients or to do liquid biopsies and choose appropriate ALK inhibitors according to their particular tumor genotype.Everything depends on the results of different trials that are ongoing and also on the activity [on patients with] specific mutations. There is space for the newer ALK inhibitors; there is plenty of space.We are in a new first-line setting with alectinib for ALK-positive NSCLC. It is very important to biopsy patients after progression due to the incidence of ALK mutations, which may not be sensitive to some inhibitors but may be sensitive to others. The most exciting [data] were presented at the 2017 ESMO Congress; it was the PACIFIC trial. The PACIFIC trial really highlights the importance of immunotherapy in earlier-stage lung cancer. This is a complete change to our practice. We never really considered immunotherapy to be effective in stage IIIa and IIIb NSCLC. Now, finally, we have a treatment that we can offer to patients as an adjuvant treatment after chemoradiation. Unfortunately, in stage IIIa and IIIb disease, the cure rate is still very low. If we can improve the cure rate, then that is great.