New Treatment Strategies Emerge for Non-Small Cell Lung Cancer

Philippe Bishop, MD

The treatment of patients with non-small cell lung cancer (NSCLC) who harbor an actionable mutation in EGFR or ALK continues evolve, as clinical trials begin exploring next-generation agents and combination strategies.

Two studies recently published in The Lancet Oncology highlighted this theme. In the first, erlotinib (Tarceva) was explored with or without bevacizumab (Avastin) as first-line therapy for patients with advanced, non-squamous NSCLC harboring an EGFR mutations.¹ The second focused on the next-generation ALK-inhibitor alectinib, which demonstrated promising activity in patients with crizotinib-resistant ALK-rearranged NSCLC.²

In 2013, alectinib received an FDA breakthrough therapy designation as a treatment for patients with ALK-positive NSCLC. Additionally, in July 2014, alectinib was approved in Japan as a treatment for patients with ALK-positive NSCLC.

To gain a better understanding of these studies, OncLive interviewed Philippe Bishop, MD, vice president of clinical development at Genentech, the company that manufactures alectinib, erlotinib, and bevacizumab.

OncLive: Can you discuss results from the phase II study of erlotinib with or without bevacizumab?

Bishop: One hundred and fifty individuals with these untreated EGFR mutation-positive NSCLC were included in this study. They were randomized to receive either bevacizumab with erlotinib, which enrolled 75 patients in that arm, or erlotinib alone, which enrolled 77 patients.

This study was a comparative study, so it was looking for whether or not bevacizumab was adding additional benefit to what was already described for erlotinib in EGFR-mutated patients. And there, what we found was actually that the patients that received the combination treatment lived 6 months longer without their disease progressing (progression-free survival) compared to erlotinib alone. In the erlotinib group, the median was 9.7 months and that compared to 16 months on the bevacizumab-erlotinib combination.

That was a substantial improvement. The hazard ratio on that was 0.54 and it was highly significant with a P value of .0015. And this represents a 46% reduction in the disease progressing and that’s actually very significant.

The safety profile of erlotinib and bevacizumab was actually manageable compared to the traditional chemotherapeutic agents that we use. This offers an opportunity to treat individuals in an effective way without some of the concerns that sometimes comes with the chemotherapy.

What can community oncologists take away from these results?

The risk-benefit analysis of this, in our view, would be favorable and I would think that for the practicing physicians that it could potentially offer a new opportunity, a new treatment combination for patients that would be suitable to receive those agents.

It’s important to note that the combination is not yet approved in the US, although both agents are available on the marketplace. This trial for us is an important component of our development program that allows us to then assess the possibilities for us to make this widely available to patients.

What are the next steps for the combination?

We’re looking right now at how we can bring these results into a dialogue with the regulatory authorities for potential labeling. We’re evaluating our options with the health authorities at this point but we also have ongoing randomized clinical trials in the US with the cooperative groups that we view as important studies to further delineate what this combination can do for patients with EGFR-mutations.

Previously, we have explored the combination of bevacizumab and erlotinib in unselected patients. This is before we understood the importance of EGFR mutations for agents like erlotinib. These trials showed a benefit in patients but the signals we were seeing were marginal at best. And as part of our program, we knew after these trials that pursuing further development with selection would be desirable. This is in part why this trial was designed.

Can you discuss the next steps for alectinib and, if approved, the impact it will have for patients?

Alectinib not only received breakthrough designation, it also is approved in Japan now, as of July of this year. This approval is an important step forward. This treatment penetrates the CNS, which I think is a very important characteristic of this drug. The brain is the secondary site of NSCLC and in this instance alectinib then penetrates the brain and offers some advantages over available ALK inhibitors.

With that in mind, we’re currently pursuing a clinical development program that will hopefully lay a path towards regulatory interactions and approval and availability throughout the world and we have two ongoing phase II studies in people whose tumors have progressed on crizotinib that are ongoing currently.

We expect results later this year. I know that even at the end of the month, there will be an update in response rate for individuals with CNS metastasis that will be presented in Chicago at the multidisciplinary meeting. We also have a head-to-head phase III study called ALEX against crizotinib that is currently recruiting patients.

Can you discuss the safety and activity of alectinib in patients with crizotinib-resistant ALK-rearranged NSCLC?

It is important to note that this is a diagnostically driven treatment for patients that are ALK mutated or have ALK-positive NSCLC. The program has yielded information from our phase I/II dose finding studies that show that alectinib can shrink tumors in 55% of patients who have ALK-positive tumors who became resistant to crizotinib.

Usually when we see individuals becoming resistance to a drug with a particular mechanism of action, it’s unusual to be able to overcome the mechanisms for escape. Here our ALK inhibitor is further differentiated in that it inhibits the kind of mutations that arise in the crizotinib treated individuals. By virtue of the various kinases that alectinib inhibits it also inhibits the kinases that get turned on after exposure to crizotinib. This is an important component to this medicine.

What was interesting to me was that the study also included 52% of individuals with progression of the disease in the brain, which again is a common site of relapse for patients with ALK-positive NSCLC. The 55% response rate that we saw, knowing that 52% of those individuals were also individuals who had disease that had spread to the brain, is actually very encouraging.

References

1. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy inpatients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study [published online August 28, 2014]. Lancet Oncol.
2. Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study [published online August 19, 2014]. Lancet Oncol. 2014;15:1119-1128.