Sequencing Issues Abound as ALK+ NSCLC Armamentarium Expands

Thomas E. Stinchcombe, MD

Treatment for patients with ALK-positive non—small cell lung cancer (NSCLC) has come a long way since the FDA approval of crizotinib (Xalkori), said Thomas E. Stinchcombe, MD, and with more ALK inhibitors in the pipeline, the challenge of finding the ideal sequence of these agents has become more pronounced.

“We know that this is a small subset of patients [with NSCLC], but it’s a very important subset, and we have made great therapeutic advances recently,” said Stinchcombe, a thoracic oncologist at Duke Cancer Institute. “We’re in an area of rapid drug development, but the optimal sequence is still unknown.”

In 2011, crizotinib became the first ALK inhibitor to receive regulatory approval for the first-line treatment of patients with ALK-positive NSCLC, and although efficacious, many patients usually stop responding to the drug after about 1 year on therapy. This landmark approval for frontline ALK-positive NSCLC was followed by ceritinib (Zykadia) and alectinib (Alecensa), both in 2017.

Updated data from the phase III ALEX trial showed that the median progression-free survival (PFS) with alectinib was 34.8 months compared with 10.9 months observed with crizotinib.¹ Furthermore, alectinib was shown to have activity in patients with CNS metastases. In this subgroup, the median PFS with alectinib and crizotinib was 27.7 months and 7.4 months, respectively.

“Of the 3 agents, I tend to use alectinib,” Stinchcombe said. “I believe that alectinib has become the standard of care based on these phase III trials.”

However, more inhibitors have emerged in the treatment paradigm in recent years. Brigatinib (Alunbrig) was granted an accelerated approval in April 2017 for the treatment of patients with metastatic ALK-positive NSCLC who are resistant to prior crizotinib. Yet, the agent is being explored upfront.

When compared with crizotinib in the phase III ALTA-1L trial in patients with ALK-positive disease who had not previously received an ALK inhibitor, brigatinib led to a significantly longer PFS.² Specifically, the PFS rate was 67% and 43% with brigatinib and crizotinib, respectively, and the objective response rate was 71% with brigatinib versus 60% with crizotinib. Moreover, updated data presented at the 2019 ASCO Annual Meeting showed that brigatinib improved health-related quality of life (QoL) and prolonged the duration of improvement in global health status/QoL. ³

Emerging agents, such as ensartinib and repotrectinib (TPX-0005), are also showing early promise.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Stinchcombe discussed the numerous ALK inhibitors available in the treatment of ALK-positive NSCLC, ongoing efforts to combat resistance, and sequencing challenges that have emerged.

OncLive: What does the current treatment landscape look like for patients with ALK-positive disease?

Stinchcombe: Initially, we had crizotinib approved for use as first-line therapy. Since then, there has been several trials [that have read out] and second-generation agents have become the standard of care. Specifically, there's ceritinib and alectinib that are approved. Then, we are anticipating that brigatinib will be approved [in the first-line setting] sometime in 2019.

There are 2 phase III trials that compared alectinib with crizotinib; it showed an impressive difference in PFS. Importantly, [the agent] also prevented the development of brain metastases, which we have known has been a big problem for all patients with NSCLC—but particularly for patients treated with crizotinib, because they have poor blood—brain barrier penetration. Also, in longer-term follow-up, the PFS with alectinib was 36 months, which was quite remarkable. Therefore, it sets a very high standard for future drug development.

Could you expand on the promise of brigatinib in the frontline setting?

In the second-line setting, brigatinib had a very impressive PFS of 16 to 17 months, which is higher than some of the other trials. Granted, cross-study comparisons are always very hazardous. Then, recently, a phase III trial compared brigatinib with crizotinib, and brigatinib showed a statistically significant improvement in PFS. The current plan is to wait for those data to mature and then [the drug manufacturer will] file for approval. Then, that might become another second-generation ALK inhibitor that's available for use in the first-line setting.

If approved as a first-line therapy, how might this agent impact sequencing?

If approved, the question for clinicians will be whether they will use brigatinib versus alectinib, and that’s going to be a challenging decision. Most of us will look at the very prolonged PFS with alectinib and have great confidence in that. We don't know [what the long-term PFS data looks like with brigatinib] because [the data are] still immature; I believe that the efficacy is ambiguous at this time.

[Healthcare providers] will look at some of the toxicities with each of the drugs and see which one maybe has a slightly better toxicity profile, and then familiarity and habit [tend to] enter our treatment decisions. Importantly, [brigatinib could] be another option for patients. As we get more options, we can sometimes select specific patients for specific drugs.

How do the toxicity profiles differ between brigatinib and alectinib?

For alectinib, [toxicities are] pretty mild with some [increases in] liver function tests, some increases in creatine phosphokinase (CPK) [levels], and then some patients will have mild fatigue. With brigatinib, to date, there can be some episodes of hypertension and early-onset pulmonary symptoms that you have to be cautious of; that's why the drug is given 90 mg daily for the first week and then it is escalated up to 180 mg.

However, many of these [events occur] in the first 1 or 2 weeks of therapy. [Patients] can also experience an increase in CPK. I believe that they have very similar toxicity profiles with the exception of pulmonary events, which are unique to brigatinib.

What data have we seen with ensartinib or repotrectinib in ALK-positive NSCLC?

The data for both ensartinib and repotrectinib have shown early promise. A phase III trial of ensartinib compared with crizotinib [has been completed]. It's very interesting that we're going to have such a large number of drugs for a small patient population. One of the [efforts] that might help us is that the National Cancer Institute has launched an ALK protocol, where patients who progress on a second-generation ALK TKI will undergo a biopsy and then their treatment assignment may be based on the presence of a mutation, or if they don't have a mutation, an ALK inhibitor will be compared with chemotherapy. A large national trial may help us [determine how to best] sequence these agents.

How does the third-generation inhibitor lorlatinib (Lorbrena) fit into the paradigm?

As we moved second-generation inhibitors into the first-line setting, what we found was that the mechanism of resistance sort of changed and there were more ALK mutations that are driving the resistance, particularly the G1202 resistance mutation.

Preclinically, lorlatinib demonstrated activity against most of the ALK resistance mutations. Then, clinically, it showed [encouraging] response rates and median PFS in patients who progressed on a second-generation ALK TKI or on 2 prior ALK TKIs. Therefore, I believe that this is a valuable therapy. As we use our more potent second-generation [inhibitors] in the first-line setting, we'll [eventually] need to transition [patients over] to another ALK-targeted therapy.

What strategies are you using to combat resistance in your practice?

A couple of things can be done, because I believe there are equal arguments for several different therapies. In patients who receive alectinib in the first-line setting, the thought is that if we do a biopsy, we might be able to detect ALK and triage patients based on their mutation status. Some [of us] are using circulating tumor DNA (ctDNA), which is helpful if it's positive. Others are not doing biopsies because there's not a treatment assigned with a specific biopsy and the data have not been proven in a prospective trial in a large number of patients. Then, [some of us are turning] to chemotherapy. These are very good prognosis patients, so many people will sequence through multiple therapies. Right now, we’re trying to figure out what the best second-line therapy is.

What is the hope for next-generation sequencing (NGS) in this space?

The hope is that we are on the cusp of using NGS in the detection of ALK to select treatment. Historically, we've had trouble getting tumor biopsies and completing the test. Fluorescence in situ hybridization had some inherent problems in terms of effectiveness, false positives, and false negatives. Sometimes we use NGS as a confirmatory test. The ctDNA helps you if it's positive, but it obviously doesn't if it's negative.

What are some key challenges faced in ALK-positive disease?

In ALK-positive patients, we continue to struggle with CNS disease. Some of these patients will progress in the CNS. We’ve recently adopted more stereotactic radiosurgery (SRS) as a potential way to [combat] the brain metastases. We're really trying to avoid whole brain radiation because of neurocognitive effects in this patient population. Now that the survival is improving, [these effects have] an impact on patients' quality of life.

Also, we still continue to be, or at least I continue to be, intrigued with the concept of oligoprogression, where if the patient receives alectinib and maybe they have 1 spot in the lung that's progressing. Can I do a course of SRS to that 1 progressive lesion and then continue the duration of alectinib? We want to make the most out of each line of therapy.

References

1. Camidge DR, Peters S, Mok T, et al. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC. J Clin Oncol. 2018;36(suppl 15, abstr 9043). doi: 10.1200/JCO.2018.36.15_suppl.9043.
2. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379(21):2027-2039. doi: 10.1056/NEJMoa1810171.
3. Campelo RG, Lin Hm, Perol M, et al. Health-related quality of life (HRQoL) results from the ALTA-1L: phase 3 study of brigatinib vs crizotinib as first-line (1L) ALK therapy in advanced ALK+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15, absr 9084). doi: 10.1200/JCO.2019.37.15_suppl.9084.