Liu Looks Beyond Resistance in ALK-Translocated NSCLC

Stephen Liu, MD, addresses the use of available therapies and the methods of overcoming acquired resistance in patients with ALK-positive non–small cell lung cancer.

Stephen Liu, MD

Responses to targeted therapies, though effective for patients with ALK translocations, are generally fleeting, said Stephen Liu, MD, adding that the research that was done to address resistance to treatment with crizotinib (Xalkori) now needs to be replicated following alectinib (Alecensa).

Although alectinib is the new standard of care in the frontline setting of ALK-positive non—small cell lung cancer, newer agents such as brigatinib (Alunbrig), lorlatinib, and ensartinib could potentially shift the landscape. As frontline treatment evolves, so does the picture of resistance, said Liu, an associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center.

“It’s a moving target, so to speak,” he added.

OncLive: What do we know about the treatment of ALK-translocated NSCLC?

In an interview during the 2018 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Liu addressed the use of available therapies and the methods of overcoming acquired resistance in patients with ALK-positive NSCLC.Liu: Patients with ALK-positive NSCLC harbor ALK rearrangements. There are a couple of different [treatment] options in the frontline setting. We have 3 FDA-approved drugs in the United States: alectinib, crizotinib, and ceritinib (Zykadia). Based on the ALEX trial findings, alectinib makes a compelling case to be the de facto standard of care. It wasn't compared directly with ceritinib, but it became the gold standard in the frontline setting based on the magnitude of benefit and tolerability.

That is bound to change, and if we do our job right, it should change. We expect frontline results from first-line brigatinib, lorlatinib, and ensartinib studies. Hopefully, those numbers will continue to improve. What we're faced with now is acquired resistance.

Acquired resistance remains the biggest challenge in the clinic. While we expect responses from most patients with targeted agents, we also know that those responses are transient. Eventually, tumors evolve and become resistant to the treatments that were initially working. We need newer studies and agents to help further care after resistance.

We have 3 approved drugs in the second-line setting. However, those are based on post-crizotinib data. Now that alectinib [has been] moved to the frontline setting, what to use after alectinib becomes our biggest question in the clinic. We have a little bit of evidence [to suggest] activity with ceritinib after alectinib based on the ASCEND-9 study. It's a small study based in Japan with a response rate of 25%.

What are the data surrounding these agents?

The newer investigational drugs, such as ensartinib and lorlatinib, have shown pretty robust responses despite multiple lines of therapy. As we move those drugs further up, resistance will change. If we look at resistance after crizotinib, we expect solvent-front mutations in about one-quarter of patients. If you start with alectinib or ceritinib, those mutations [will manifest] in about half of patients. Every time we change the frontline treatment, the resistance picture changes as well.Brigatinib was the most recently FDA-approved agent in the second-line setting post-crizotinib. It maintains activity in vitro in the presence of a lot of resistance mutations, so [there is a case to be made to] use it in the salvage setting after other tyrosine kinase inhibitors (TKIs). However, most of that evidence is preclinical. It hasn't been validated in the clinic. Those efforts are ongoing.

Ensartinib and lorlatinib maintain activity in the presence of many solvent-front mutations. They have very high central nervous system penetration and a favorable toxicity profile. Those are requirements for the newer drugs. Ensartinib has shown response rates of about 80% in TKI-naïve patients. Response rates after crizotinib are pretty similar at about 72%. Ensartinib has shown activity in heavily pretreated patients, following at least 2 prior TKIs. These patients have genomically complex tumors, but experience response rates approaching 25%.

Will we ever have an ALK inhibitor equivalent to osimertinib (Tagrisso)?

Were there any promising combinations for ALK-positive disease presented at the 2018 ASCO Annual Meeting?

Lorlatinib has shown response rates over 40% with at least 2 prior TKIs. It certainly makes a compelling case to use those as salvage treatments. One has to wonder how effective [these agents] would be in the frontline setting. We're already seeing progression-free survival of over 2 years with alectinib. If we start with agents with an even broader range of activity, like lorlatinib and ensartinib, the sky [may] be the limit [with] those.I think so. Resistance [to] ALK TKIs is fundamentally different from EGFR [TKIs]. While they parallel [each other in many ways], resistance to [EGFR TKIs] is primarily mediated through T790M. We don't have an analogous ALK [mutation]. While there are gatekeeper mutations, there are about a dozen different point mutations. There isn’t a dominant [mutation] to target. The resistance patterns are very heterogeneous, which makes [treatment] very difficult. One can certainly envision a future where we can identify a mutation through next-generation sequencing (NGS), and use that very sophisticated rationale to choose our TKIs. Right now, it's just not ready. Most of the use remains empiric. We have to believe we'll get there though.Immunotherapy has made an undeniable impact in NSCLC, but patients whose tumors harbor driver mutations have been relatively spared of those benefits. For ALK-positive lung cancer, we know that response rates to salvage PD-1 inhibitors are pretty low. At the 2018 Annual ASCO Meeting, we saw combinations of avelumab (Bavencio) with crizotinib, avelumab with lorlatinib, and atezolizumab (Tecentriq) and alectinib.

These were single-arm studies that were mostly looking at safety. They showed impressive efficacy, although [they are already efficacious] on their own. It's very difficult to make any conclusions based on these studies.

The safety signal was more eye opening. When you take 2 drugs that are very well tolerated and combine them, you can have unexpected toxicities. The study of avelumab and crizotinib was notable because it showed a dose-limiting toxicity rate of 40%. It was not a safe combination. Avelumab and lorlatinib looked more tolerable, but there are still significant toxicities with this combination.

Are there any other agents that are being tested in combination with ALK inhibitors?

Is there other research that you would like to share?

What will the role of chemotherapy be as more of these novel agents come forward?

The same applies to atezolizumab and alectinib. There is certainly rationale for that. When we [gave] alectinib, we saw an increase in the infiltration of CD8-positive T cells in the tumor. This combination may be more than just additive. There may be some synergy between these molecules. Right now, I'm not convinced of the safety signal. I would stress that these are investigational, and the safety of these combinations needs to be confirmed before they are used in practice. There has been some interest in targeting Hsp90 alone or in combination with ALK inhibitors. By targeting certain chaperone proteins, we may be able to block that signaling cascade more effectively.ALK transcends tumors. We think of ALK fusions as present in NSCLC, but we can see it across oncology. We recently reported a case in a patient with pancreatic cancer and a case of a patient with differentiated thyroid cancer. The more we apply NGS, especially RNA sequencing across oncology, the more we're going to find. The financial implications of broad molecular testing are certainly important; however, if we keep testing, we're going to find ALK in many other tumors. For those patients, it's going to make a big difference. As more novel agents come along, chemotherapy gets bumped down. Dr D. Ross Camidge did some retrospective work showing that ALK-positive patients benefit more from pemetrexed-based therapy. It’s not the chemotherapy of the past; it’s relatively well tolerated. It plays a role for a lot of patients, though there are better options upfront. I would still put chemotherapy ahead of immunotherapy for ALK-positive lung cancers, though.