Novel Drugs Revolutionizing ROS1+ and ALK+ NSCLC

Katie Kerrigan, MD

Following the 2016 FDA approval of crizotinib (Xalkori), agents designed to target ROS1-mutated advanced non—small cell lung cancer (NSCLC) have been rapidly emerging and showing impressive signals of activity, said Katie Kerrigan, MD.

For example, the FDA approved entrectinib (Rozlytrek) in August 2019 for the treatment of adults with ROS1-positive, metastatic NSCLC, based on impressive response rates in an integrated analysis of the STARTRK-2, STARTRK-1, and ALKA-372-001 trials. Updated findings from the pooled analysis presented at the 2019 ESMO Congress showed that entrectinib demonstrated a 79.2% objective response rate (ORR) in this patient subgroup. With an additional 5 months of follow-up since the primary analysis, 2 more patients with ROS1-positive disease achieved complete responses (new total = 5) and the median duration of response exceeded 2 years in the ROS1-positive group.

“The approval [of crizotinib] basically revolutionized the treatment of this disease,” Kerrigan said. “Crizotinib quickly became the frontline agent for ROS1-mutated advanced NSCLC. The approval opened up a number of both basic science and translational clinical research. Now, we have more than 5 agents to treat ROS1-mutated disease. It really laid the framework for the management of this disease."

Similarly, the ALK-positive NSCLC space has shown growth over the years with the introduction of ALK TKIs beyond crizotinib, said Kerrigan.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Kerrigan, a hematology/oncology fellow at the University of Utah School of Medicine, discussed novel agents emerging in both ROS1- and ALK-mutated NSCLC and the sequencing challenges for these patients.

OncLive: Could you discuss the design and takeaways from the PROFILE 1001 study of crizotinib?

Kerrigan: PROFILE-1001 was the initial phase I study evaluating crizotinib in heavily pretreated patients with ROS1-mutated advanced NSCLC. Patients in that study had generally received multiple lines of chemotherapy prior.

Thankfully, patients with brain metastases were included [in PROFILE 1001], which is important because these patients are often excluded from other clinical trials, even though [ROS1-mutated patients often have brain metastases].

Crizotinib is very effective in ROS1-mutated disease. These patients had long progression-free survival and fantastic overall survival (OS). At the updated result, they lived over 4 years on this drug. It revolutionized the management of patients with ROS1-mutated disease.

What other options have emerged for patients with ROS1-mutated NSCLC?

The second player that came on the block was ceritinib (Zykadia), but it isn't really used in clinical practice.

The newest agent that gained FDA approval in August 2019 is entrectinib. Entrectinib showed great responses, and it may become the new frontline standard. Lorlatinib (Lorbrena) and repotrectinib, the newest [agent], are also being studied in earlier-phase trials for patients who have relapsed on one prior ROS1 TKI. Therefore, we have multiple options, which is a great space to be in.

You said entrectinib may become the next frontline therapy. What is the benefit seen with entrectinib over crizotinib?

There are two reasons entrectinib will probably triumph crizotinib and become the new first-line standard of care. Entrectinib had slightly higher ORRs, so more patients are likely to benefit from the agent. Also, it has higher intracranial activity, so it is likely beneficial for patients with brain metastases.

How do the toxicity profiles of entrectinib and crizotinib differ?

They are pretty similar. You worry about nausea with crizotinib, as well as some visual adverse events and some liver function abnormalities.

I honestly have not used entrectinib in the clinic yet because ROS1-mutated disease is so rare that I haven't had a new patient present with it. Entrectinib was well tolerated [in clinical trials], so long as insurances approve it, it will become the new standard.

What does patient selection look like in the frontline space?

Once I know a patient has ROS1-mutated disease, I weigh my treatment decision on whether or not they have brain metastases. If they do, I would prefer entrectinib upfront based on those higher responses in the brain.

If they don't, crizotinib does remain a good first-line option, but it will depend on out-of-pocket costs for patients and insurance approval.

What does sequencing look like after patients receive crizotinib?

After crizotinib, it is important that we re-biopsy these patients and try to determine their mechanism of resistance. If it appears that they still have a ROS1-dependent mechanism driving their cancer, both lorlatinib or a clinical trial looking at the use of repotrectinib are good options. Lorlatinib and repotrectinib have been shown in the second-line setting to have good efficacy at about a 30% to 40% response rate.

Could you expand on some of the work that has been done with lorlatinib?

A phase II study was published in The Lancet Oncology in 2018 looking at lorlatinib in the later-line settings both in ALK- and ROS1-mutated patients. The ROS1 cohort was much smaller than the ALK cohort, simply by the nature of it being a rarer disease. It did show that the ORRs were around 30%, so it does seem to be efficacious. We don't have any phase III data yet.

What are some of the biggest unmet needs that still remain in this space?

Patient selection is still [lacking]. We are unsure [how to select treatment] because entrectinib is very new. Is it that much more superior to crizotinib? We need more information to determine which will be the standard.

I hope to see later-line phase II and III studies with repotrectinib, because it looks like it will have the highest efficacy. In the phase I studies reported at the 2019 ASCO Annual Meeting, it had a 100% ORR in the brain, which is incredible. Perhaps repotrectinib will eventually move to the frontline setting but we don't have that data yet.

Hopefully more data will come out the future as repotrectinib appears to be very efficacious in both the brain and the body. The numbers we are seeing in the early-phase studies [look superior to] all other agents [in this space].

What other agents under exploration would you like to discuss?

For ALK-positive NSCLC, ensartinib is [being explored] in clinical trials. That is a third-generation ALK TKI. We don't have a ton of data on it yet, but we do have first-, second-, and third-generation ALK TKIs in our treatment armamentarium, which is great. However, there is more to come out with ensartinib.

What recent data have read out from medical meetings in this space?

Mainly, [we are] trying to determine the appropriate sequence of the agents. Particularly in ALK-mutated disease, these patients can live a long time; we don't have OS data for the second- and third-generation ALK TKIs at this point.

It is important to know how to sequence these agents to give our patients the maximum benefit for the longest period of time. Here in the United State, alectinib (Alecensa), based on the ALEX trials, has become the frontline standard of care.

We don't know if brigatinib (Alunbrig), another second-generation ALK TKI, is that efficacious post-alectinib. There are some retrospective reviews suggesting it is not and that lorlatinib is superior.

Also, we don't know where immunotherapy comes into play. We have data showing that single-agent immunotherapy is probably not very effective, but should we combine it with chemotherapy? Should we be combining it with chemotherapy and with a VEGF inhibitor?

What is your take-home message for colleagues treating patients with ROS1- and ALK-positive NSCLC?

It is very important for patients on ALK or ROS1 TKIs, at the time of progression, to be re-biopsied to understand what is driving their resistance to that TKI. If it appears to be an ALK-dependent mechanism of resistance, our patients are probably still sensitive to later-generation ALK TKIs, and we should be using these later down the line.

There are some patients who have ALK-independent mechanisms of resistance, such as transformation of their cancer to another form called small cell lung cancer. Most likely, they are not going to benefit from continued ALK inhibition. We would need to modulate our treatment strategy based on that.

De Braud FG, Siena S, Barlesi F, et al. Entrectinib in locally advanced/metastatic ROS1 and NTRK fusion-positive non-small cell lung cancer (NSCLC): Updated integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Presented at 2019 ESMO Congress; September 27-October 2, 2019; Barcelona, Spain. Abstract 1488PD.