By Erik J. MacLaren, PhD
Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that was recently approved in the US as a second- line treatment for ALK-rearranged non-small cell lung cancer (NSCLC) after progression on the standard firstline therapeutic, crizotinib. Data from the J-ALEX trial,1 a Japanese phase 3 study directly comparing first-line efficacy and the safety of alectinib versus crizotinib, were presented at the 2016 ASCO Annual Meeting, showing that alectinib significantly increased progression-free survival (PFS) in patients.2 IASLC Lung Cancer News spoke with Alice T. Shaw, MD, PhD, from Harvard Medical School in Boston, Massachusetts, and Ranee Mehra, MD, from the Fox Chase Cancer Center in Philadelphia, Pennsylvania, to find out what these results might mean for the treatment of ALK-positive NSCLC.
Q: Is the J-ALEX study a “game changer” in terms of how we treat ALK-positive NSCLC?
Shaw: J-ALEX is almost a game changer. The results suggest that alectinib is superior to crizotinib as as first-line tyrosine kinase inhibitor (TKI) therapy, but there are some minor issues with this study that could impact extrapolation of the findings to all patients. Ultimately, we need to see the results from the global ALEX trial3 to confirm that PFS with alectinib is superior to crizotinib, and to determine the magnitude of the PFS benefit with alectinib.
Mehra: The hazard ratio (HR) of the alectinib arm versus the crizotinib arm reported at ASCO was 0.34,2 which is very impressive, so I think that J-ALEX is indeed a game changer.
Q: Should we adopt alectinib frontline routinely, even in the absence of the concomitant data from the global ALEX study?
Shaw: I think we should wait for the global ALEX results before we start using alectinib routinely as first-line therapy. I do think, however, that there are specific scenarios in which we should use firstline alectinib. Specifically, I believe alectinib can and should be used as a first-line therapy in patients who have ALK+ lung cancer and brain metastases at diagnosis, given the results from the single-arm phase 2 studies of alectinib4,5 and what we now know from J-ALEX in terms of the benefit of alectinib over crizotinib in patients with brain metastases.
Mehra: I would expect that the global ALEX results are going to be positive, based on the J-ALEX data, but there are probably pharmacogenomic differences between the populations included in these trials. Therefore, I think it is reasonable to see the global ALEX data and the exact benefit of the drug in the first-line setting before it becomes a standard of care. On a case-by-case basis, it may be something to consider now for patients with preexisting brain metastases.
Q: If alectinib becomes the standard first-line option, what do we give second- line or third-line?
Shaw: We do not know much yet about patients whose disease has progressed on first-line alectinib, but I would anticipate that 40% or 50% of these patients could have a secondary mutation in ALK that is causing resistance, such as G1202R or I1171 mutations. Other ALK inhibitors, particularly lorlatinib, do have activity against these mutations, so I envision that another ALK inhibitor could be an option in the second-line setting after progression on alectinib, depending on the resistance mechanism that is identified. Of note, ceritinib is inactive against G1202R. Chemotherapy is an option at any point, but I would argue that patients whose disease progresses on alectinib and who have an ALK resistance mutation should have another ALK inhibitor before going on to chemotherapy.
Mehra: Ceritinib is an FDA-approved agent in the second-line setting, although we do not have a lot of experience with its activity after alectinib. Anecdotally, there are case series experiences of ceritinib showing activity after failure on alectinib, so I think ceritinib is a reasonable standard option. We also have some emerging data about resistance mutations, which may help guide subsequent treatment selection. Ongoing trials of newer ALK inhibitors, such as lorlatinib and X-396, and immunotherapeutic agents are also reasonable options to explore before going to chemotherapy.
Q: The rate of baseline central nervous system metastases in the crizotinib arm of J-ALEX was almost double that of the alectinib arm. Is this imbalance a concern?
Shaw: It was a bit of a surprise to me that brain metastases were not a stratification factor for randomization in the J-ALEX study. Nevertheless, the HR for alectinib in the subgroup of patients who had brain metastases is .08, which shows a really huge benefit for this drug. In the global ALEX data, this will not be an issue, since brain metastases were a stratification factor.
Mehra: Although there was an imbalance in baseline brain metastases, the response rates of the two agents were similar. The benefit seemed to be in the PFS and the number of new events, so I do not think the imbalance in the baseline brain metastases would have affected the results too much. If performance status between the arms was imbalanced, there would have been more concern, but it was not.
Q: Should all patients with progressive disease on front-line alectinib be biopsied?
Shaw: Patients whose disease is progressing on alectinib should absolutely be biopsied because we are just beginning to understand the mechanisms of resistance to this drug. I also believe that repeat biopsies are crucial to picking the next agent for patients whose disease has progressed on first-line alectinib. We are hoping to develop liquid biopsies that can detect ALK resistance mutations in the blood and follow them serially over time. That may allow us to bypass the need for additional tissue biopsies.
Mehra: Repeat biopsies are most often done only at tertiary care and research institutions, but I think this too will soon be an emerging standard of care. As we learn more about resistance mutations, biopsies will be important for deciding which next-generation drug to use. The challenges right now are that not all community centers have a mechanism to do repeat testing and that it is not always safe to do a biopsy in pretreated patients. Cellfree liquid biopsies could soon become a routine way to get these data.
1. JAPIC Clinical Trials Information. Open-label Randomized Phase III Study of the Efficacy and Safety of CH5424802 (AF802) in ALK-Positive Advanced or Recurrent Non-Small Cell Lung Cancer with Crizotinib Control. 2013; http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-132316. Accessed June 26, 2016.
2. Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study. J Clin Oncol. 2016;34(Suppl):Abstr 9008.
3. ClinicalTrials.gov. ALEX Study: A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non- Small Cell Lung Cancer Participants. 2014; https://clinicaltrials.gov/ct2/show/NCT02075840. Accessed June 26, 2016.
4. Ou SH, Ahn JS, De Petris L, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non- Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol. 2016;34(7):661-668.
5. Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2016;17(2):234-242.