Next-Generation TKIs Continue to Impress in ALK+ and ROS1+ NSCLC


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Vamsidhar Velcheti, MD, discusses the current and emerging treatment options for patients with ALK- and ROS1-positive non–small cell lung cancer.

Vamsidhar Velcheti, MD

Molecular testing is an absolute necessity for patients with non–small cell lung cancer (NSCLC), particularly now that next-generation ALK and ROS1 inhibitors are showing such robust data, explained Vamsidhar Velcheti, MD.

For patients with ALK-positive NSCLC, alectinib (Alecensa) has been the preferred frontline standard of care since its 2017 approval. The regulatory decision was based on findings from the phase 3 ALEX trial, in which alectinib led to a 47% reduction in the risk of progression or death versus crizotinib (Xalkori). At the 2020 ASCO Virtual Scientific Program, results from the trial showed a sustained progression-free survival (PFS) advantage (HR, 0.43) and improvement in overall survival (OS; HR, 0.67) with the second-generation TKI.1

Moreover, the median investigator-assessed PFS was prolonged with alectinib compared with crizotinib in patients with baseline central nervous system (CNS) metastases, at 25.4 months versus 7.4 months, respectively (HR, 0.37; 95% CI, 0.23-0.58).

For patients with ROS1-positive NSCLC, entrectinib (Rozlytrek) has surfaced as the preferred frontline standard of care, according to findings from an integrated analysis of the phase 2 STARTRK-2, phase 1 STARTRK-1, and phase 1 ALKA-372-001 trials showcasing the systemic activity and CNS potency of the pan-kinase inhibitor.

The pooled results from the 3 trials showed that entrectinib led to a 78% objective response rate (ORR) and a median duration of response (DOR) of 24.6 months in patients with ROS1-positive NSCLC (range, 1.8 to 36.8+). Moreover, the intracranial ORR was 55.0%.

On August 15, 2019, the FDA granted an accelerated approval to entrectinib for the treatment of adults with ROS1-positive, metastatic NSCLC.2

“We’re seeing phenomenal improvements in outcomes with certain new targeted therapies. It is extremely crucial to really work these patients up thoroughly with comprehensive genomic profiling to understand the biology of these tumors better, so that we can treat them with the appropriate targeted therapy,” said Velcheti.

In an interview with OncLive® during the 2020 International Perspectives in Cancer on Lung Cancer, Velcheti, an associate professor in the Department of Medicine at NYU Grossman School of Medicine, and director of the Thoracic Med Oncology Program, at NYU Langone Health’s Perlmutter Cancer Center, discussed the current and emerging treatment options for patients with ALK- and ROS1-positive NSCLC.

OncLive®: What do the updated ALEX results mean for the use of alectinib in ALK-positive NSCLC?

Velcheti: The ALEX study was a randomized phase 3 study comparing standard 600 mg of alectinib twice daily with crizotinib, which was the prior standard of care in ALK-positive lung cancer.

We recently saw an update of the intent-to-treat (ITT) population of patients with ALK-positive NSCLC. The initial results had shown an improvement in PFS with alectinib versus crizotinib in the frontline setting. We recently saw the OS update. The 5-year survival rate with alectinib is 62.5% versus 45.5% with crizotinib, despite significant crossover. About 53% of patients who were on the crizotinib arm crossed over to receive the second-generation ALK inhibitor.

Alectinib is already FDA approved in this indication. These results are reassuring to see that there is an improvement in 5-year OS with alectinib. The OS data are still immature. At the time of the analysis, only 37% of events were recorded in the ITT population. We’ll certainly see more updates from this trial in the future, but based on what we’ve seen so far, the benefit of alectinib seems to be holding up.

Will the expanded indication for brigatinib (Alunbrig) in the frontline setting impact the use of alectinib?

It’s difficult to say because these agents haven’t been compared head to head. The safety and long-term OS data we’re seeing with alectinib are certainly encouraging. However, this was in comparison to an older-generation ALK inhibitor, so it’s really hard to say how it compares with brigatinib.

Looking to the second-line setting, are mechanisms of resistance informing potential treatment approaches?

What we’re learning from ALK is quite fascinating. Understanding the mechanisms of resistance to these targeted selective TKIs helps us inform subsequent lines of treatment. When patients progress on an ALK inhibitor, sometimes they develop on-target solvent front mutations that may have differential sensitivity to various ALK inhibitors. Understanding the mechanisms of resistance and the types of mutations that might emerge on treatment are extremely informative in terms of planning subsequent treatment options.

How do you currently approach sequencing?

In the newly diagnosed setting, I have been using alectinib, based on the data from the ALEX trial. You can also use brigatinib, which is also approved by the FDA. Upon progression, I generally tend to rebiopsy patients. If it’s not clinically feasible to rebiopsy these patients, I order circulating tumor DNA-based molecular profiling to understand mechanism of resistance. Based on the mechanism of resistance, you can sequence the ALK inhibitors.

Does your approach differ for patients with brain metastases?

In patients who have ALK-positive lung cancer, especially if they have a lot of brain metastases, it is really important to consider initiating ALK-directed therapies as soon as possible to control the disease burden. Sometimes, these patients might require local interventions based on the severity of the CNS disease.

The second- and third-generation ALK inhibitors have really good CNS penetration. I generally try to avoid whole brain radiation in these patients because we see really nice CNS responses with these agents.

Shifting to the ROS1 space, what developments have we seen in this setting?

We have excellent targeted therapy options for patients with ROS1-positive disease. Crizotinib is FDA approved for patients who have a ROS1 fusion, based on the initial results of the PROFILE 1001 trial. In 2019, we saw updates from that trial. We didn’t see any major surprises here. We know crizotinib works in patients who have ROS1-rearranged lung cancers. The response rate was close to 70%, and the DOR was close to 2 years. The data continue to mature.

What’s most exciting is the data we’re seeing with newer TKIs, which are more potent than crizotinib. We saw the results of a pooled analysis of 3 different trials with entrectinib. Specifically, [these were from] 2 phase 1 dose-escalation studies and a multicenter phase 2 basket trial. The analysis included 53 patients with ROS1-positive NSCLC. In the pooled integrated analysis, which was presented at the 2018 World Lung Cancer Conference and also published by Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, in Cancer Discovery in 2017, we know that entrectinib has excellent efficacy in patients with ROS1-rearranged lung cancers, with a response rate close to 80%. Most importantly, the responses appear to be durable, with about a 2-year median DOR.

Entrectinib seems to be a very effective drug, with very nice CNS penetration. We’ve seen a response rate of approximately 70% in the brain. Entrectinib appears to be more potent with better CNS penetration [compared with crizotinib], which is highly encouraging. Entrectinib is also FDA approved for patients with ROS1-rearranged NSCLC. Because patients with ROS1-positiveand ALK-positive NSCLC tend to have a higher incidence of brain metastases, it is really important to treat patients with the most potent and CNS penetrant drug up front.

Is it too early to comment on other agents that are under investigation, such as alcotinib and talatrectinib?

I think it’s too early to comment on it or a couple of reasons. We don’t have any head-to-head comparative data, so it really makes it really hard to kind of understand [the differences between these agents]. The rarity of these subgroups, especially for ROS1, makes it really hard to do randomized controlled trials. There are several potent drugs that could potentially change the landscape. However, there might be subtle differences in terms of efficacy.

Certain types of mutations might lend itself to a particular TKI more than the other. There’s a little bit of differentiation in terms of the exact kind of fusion partners or the types of solvent front mutations that might be the resistance mechanisms for these drugs. We’re still learning. There’s a lot of opportunity for improving outcomes for these patients in the long run because we have a better understanding of the biology. All these things are really encouraging and good signs that we are making progress.

What ongoing or planned research would you like to highlight?

There are a lot of new exciting targets. KRAS, which was thought to be undruggable, is present in about 30% of all lung cancers. Now we have novel mechanisms that we can use for KRAS inhibition. We’re developing exciting new selective KRAS inhibitors for patients with KRAS G12C mutations, which could potentially change the way we manage these patients.

Also, we’re understanding the implications of various co-occurring mutations like KEAP-1, NRF-2, and LKB1. The biologies of these cancers are very different, and we are exploring new ways to overcome some of the resistance in these really tough to treat genomic subtypes of

lung cancer. At NYU Langone Health, we have a lot of ongoing trials that are addressing these issues.

What is a current challenge that you would like to see addressed?

In the past several months, we’ve had a lot of new indications. We’re better understanding the biology of lung cancer. However, if you don’t test for these mutations, then none of these things matter. It is increasingly important for us to do comprehensive genomic profiling for all our patients in order to match them with the appropriate therapeutic target.


1. Peters S, Mok TS, Gadgeel SM, et al. Updated overall survival (OS) and safety data from the randomized, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated ALK+ NSCLC. J Clin Oncol. 2020;38(suppl 15):9518. doi:10.200/JCO.2020.38.15_suppl.9518

2. FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor. FDA. August 15, 2019. Accessed August 5, 2020.

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