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Managing <i>ALK</i>+ NSCLC
My Approach for Managing Patients With Progressive ALK-Positive NSCLC

Released: January 22, 2018

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New targeted agents and emerging data are reshaping how we manage patients with ALK-positive non-small-cell lung cancer (NSCLC). In this commentary, I discuss how the latest evidence informs my treatment of patients with progressive disease on previous ALK inhibitors.

Current Treatment Options After Disease Progression on Crizotinib
For patients with ALK-positive NSCLC progressing on the first-generation ALK inhibitor crizotinib, there are currently 3 second-generation ALK inhibitors with FDA approval: ceritinib, alectinib, and brigatinib. All have good activity in patients who failed crizotinib, with ORRs ranging from 40% to 55%. The median PFS is 5-7 months with ceritinib, 9 months with alectinib, and a notably longer 13 months with brigatinib. Although crizotinib shows some efficacy in the CNS the CNS is nonetheless a common site of recurrence for patients being treated with this agent. Fortunately, these 3 second-generation ALK inhibitors all penetrate the CNS. In the setting of progressive disease, the brain ORR reported with ceritinib is approximately 40% and ranges from 42% to 67% with brigatinib, whereas alectinib offers a brain ORR of 57% to 75%.

Each of these 3 agents has a different safety profile. Ceritinib is associated with primarily grade 1/2 GI toxicity (ie, nausea and diarrhea); however, the ASCEND-8 trial recently reported that GI events were markedly reduced by giving patients the lower dose of 450 mg with a low-fat meal. By contrast, alectinib is primarily associated with grade 1/2 myalgia, edema, and fatigue. Brigatinib is associated with an unusual acute onset shortness of breath that is manageable through dose reduction and awareness on the part of both physicians and patients.

Currently, we do not have any randomized clinical trials comparing the second-generation ALK inhibitors. Consequently, the choice of which specific ALK inhibitor to recommend should include consideration of the patient’s comorbidities and each drug’s safety profile.

Biopsy at Progression May Aid Treatment Decisions
Given the limited available information to guide selection among these 3 ALK inhibitors, some physicians request a postprogression biopsy with molecular testing to identify potentially relevant resistance and sensitivity mutations in ALK and other potential bypass pathways. I find this approach useful because, for example, if a mutation that is resistant to alectinib (eg, ALK I1171T/N/S) is identified, I will not consider alectinib.

In patients with crizotinib-resistant disease, the resistance mechanism can be ALK dependent or ALK independent. ALK dependent resistance is due to either ALK amplification or a new mutation in the ALK protein’s kinase domain. ALK-dependent mechanisms have been observed in up to 35% of crizotinib-resistant tumors. By contrast, ALK-independent mechanisms bypass ALK through alternative cellular pathways such as EGFR pathway activation and others.

Some physicians do not consider a postprogression biopsy and testing to be necessary. This is because studies have reported that ceritinib and brigatinib are each effective in the second-line setting, independent of the mechanism of ALK resistance. In my opinion postprogression biopsy helps my selection of a second-line ALK inhibitor or alternative therapies. Small cell transformation has now been reported in patients with progression on an ALK inhibitor. Discovering small cell transformation will alter my therapy selection. In addition, should an ALK-dependent mechanism be identified that is predictive of resistance to one of the 3 available options as described above, an alternative investigational ALK inhibitor can be considered.

Progression After Multiple Lines of ALK Inhibitor Therapy
It is interesting to consider the scenario where a patient experienced progression on crizotinib, switched to another ALK inhibitor, and then experienced progression on the new ALK inhibitor. Should these patients be switched to yet another ALK inhibitor? Presently, the strongest data we have in this setting are for the investigational ALK inhibitor lorlatinib. A recent phase I trial evaluated lorlatinib in patients with ALK-positive NSCLC and reported that the ORR was 42% among patients who had received ≥ 2 previous ALK inhibitors compared with 57% among those with only 1 previous ALK inhibitor.

Another very interesting concept related to disease progression after multiple ALK inhibitors was reported by Dr. Shaw and colleagues who recently published a case report looking at clonal evolution in a patient with ALK-positive NSCLC over the course of multiple ALK inhibitors. This patient had developed resistance to first-line crizotinib because of the ALK kinase domain mutation C1156Y. After switching to lorlatinib, her tumor initially responded but then progressed and exhibited development of an additional ALK L1198F mutation. This new mutation conferred lorlatinib resistance while also resensitizing her tumor to crizotinib, despite the presence of the original C1156Y mutation. This case report illustrates why I think that our standard of care will evolve to doing routine postprogression tissue or liquid biopsies for these patients to allow for selection of specific ALK inhibitors based on their different sensitivity and resistance profiles and the patient’s specific ALK mutation profile. In addition, future ALK mutation patterns may also be quite different in patients treated with frontline alectinib compared with patients treated with frontline crizotinib with potential impact on our choice of subsequent therapy. We will only gain this information through biopsies and testing.

In my current practice, when I encounter a patient who is progressing on alectinib or ceritinib after crizotinib, I do a biopsy. If I find a known mutation explaining why the patient is resistant to his or her current ALK inhibitor and/or a mutation that predicts sensitivity to ceritinib or brigatinib, I will consider switching the patient to those latter options. Presently, we have only anecdotal information on whether, for example, brigatinib works after alectinib, but I consider it reasonable to try a third ALK inhibitor assuming the patient is not in a rapid clinical decline. When proceeding to a third ALK inhibitor, I follow my patients very closely with a follow-up imaging no later than 2 months after starting therapy. I prefer to treat these patients on clinical trials and would consider an ALK-directed clinical trial to be the better option for them.

Presently, for my patients with disease progression after 3 ALK inhibitors, I prefer to move the patient to standard chemotherapy. It is important to bear in mind that immunotherapy is not as active in ALK-positive NSCLC as it is in patients without targetable driver mutations, so I usually do not use immunotherapy until I have exhausted other available therapy options.

To see what 5 other lung cancer specialists would recommend for patients with ALK-positive NSCLC in different clinical scenarios, visit the NSCLC Decision Support Tool.

Your Thoughts
How are you managing patients with ALK-positive NSCLC in your practice? Do you biopsy those patients who are experiencing progression? Please share your experiences and thoughts by joining the conversation in the comments box below and responding to the polling question at the right of your screen.