Editor’s Note: This interview first aired on Lung Cancer Considered on April 19. What follows is the second half of the interview—a discussion of the ALINA trial—between Lung Cancer Considered host Narjust Florez, MD, and investigator Benjamin Solomon, MBBS, FRACP, PhD. The interview has been edited slightly for length and clarity. Find Part 1, Adjuvant Alectinib for ALK+ NSCLC: An Interview with Dr. Benjamin Solomon, here. For more information on the ALINA trial and the subsequent approval of alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer, see ALINA Trial Leads to New Treatment Option for Early-Stage ALK+ NSCLC.
Dr. Florez is Associate Director of the Cancer Care Equity Program and Assistant Professor of Medicine at the Dana-Farber Cancer Institute and Harvard Medical School, Boston. Benjamin Solomon, MBBS, FRACP, PhD, is a clinician-scientist at Peter MacCallum Cancer Center in Victoria, Australia. His clinical and translational research has identified new treatments, changed the standards of care, and improved outcomes for patients with lung cancer.
Dr. Florez: As a person that treats younger women, many of them with ALK-positive non-small cell lung cancer. I just had a conversation with a 36-year-old patient, Ben. She said, “I have two young children. What else can I do to decrease the chances of this coming back? Because when I go to bed, that’s the last thing I think about.” Alectinib is an option for these patients, and we need to remember the patient perspective. Yes, we want overall survival data. That’s the gold standard. But for that 36-year-old waiting for this drug to be approved, disease-free survival matters to her.
Dr. Solomon: I think we talk about the meaning of endpoints, and we have many discussions about what disease-free survival means. Is it sufficient? Do we need overall survival? I think at the end of the day, what you just said about the importance of the patient perspective and what matters to the patient really is what counts. Time without disease. Time without brain metastases. These are meaningful endpoints. No, not meaningful endpoints. They’re meaningful things to patients, and we do need to remember that. If the disease doesn’t come back, that’s really the opportunity for survival. To me, disease-free survival and protection from CNS metastases are absolutely meaningful endpoints and factors that should impact choice of therapy.
Dr. Florez: Thank you, Ben. I know that knowing you, that everything you do, you always take the patient perspective. This is a great segue for my next question because this trial compares alectinib for 2 years versus chemotherapy. What were the thoughts when you were considering that design, which is different than ADAURA where some patients could get chemotherapy and then got osimertinib? How was that decision made?
Dr. Solomon: That’s a great question, and that was tough. Or rather, it was a really involved discussion, I should say. There was a lot of debate about whether the study should be chemotherapy followed by alectinib or the head-to-head comparison of alectinib versus chemotherapy. I think there are good arguments for both designs, but the feeling was, in the advanced setting, we really have shown that ALK inhibitors or tumors with ALK rearrangements are really exquisitely sensitive to treatment with ALK-TKIs. The benefit from ALK inhibitors is so much more than the benefit from chemotherapy, so there was a real opportunity to do a head-to-head design.
There was some discussion about whether there should be a third arm of chemotherapy followed by alectinib, but we ended up with the two-arm study. I think it is important to acknowledge that perhaps this is a limitation of the study—that we haven’t evaluated the role of giving chemotherapy plus alectinib.
Dr. Florez: I think there are pros and cons. We know the benefit of chemotherapy is borderline, but we also know the long-term follow-up data for chemotherapy. So, I think as you say, you probably went back and forward on that. So, as we talk about how living with lung cancer is not only about living longer but also about living better, I think is the time to talk about the toxicity in the trial. What were some of the most common toxicities, and how many patients required dose reduction or discontinuation on ALINA?
Dr. Solomon: The toxicity profile was similar to what we’ve learned about alectinib in the advanced setting. The most frequent toxicities were asymptomatic elevations in liver function tests and in creatinine kinase. In terms of symptomatic toxicities, constipation, muscle aches, and weight gain were the main toxicities.
In terms of patients that required dose interruption or dose reduction, this is about 25% of patients on the study, but only 5% of patients required discontinuation. A lot of trial presentations end with, “The treatment was generally well-tolerated.” I’ve learned that that’s not really an adequate statement. These toxicities are important, particularly when patients experience them for years—2 years in the case of the ALINA study—it must be said that these toxicities improve compared to the toxicities that we see with chemotherapy, which was the control arm of the study.
Dr. Florez: I think that’s an important point, because the patients on the targeted therapy have been on it for 2 years when the chemotherapy is four cycles for about 12 weeks. So we know that these drugs have some toxicity. I don’t think anyone would be able to tolerate 2 years of chemotherapy… Duration of therapy is so important. Now I have a question related to stage, because we talk about how the patients were stratified by stage. Do you see a clear benefit or difference between the patients, for example, stage III versus stage I, like we have seen in other adjuvant studies?
Dr. Solomon: This is probably a little less clear in ALINA. We saw a similar magnitude of benefit across the stages. In stage IB, the hazard ratio was 0.21. In stage II, it was 0.24, and in stage IIIA, it was 0.25. One note was that the 95% confidence interval for the hazard ratio in the stage 1b population was pretty wide. It was 0.02 to 1.84. I think more than anything else, this reflected the small number of patients in the IB population, 26 patients compared to 92 with stage II and 139 with IIIA. So, maybe a little bit hard to say with the numbers, but at least in terms of hazard ratios, the benefit seems to be consistent. Of course, it’s important to point out that these stage groups are by the 7th edition of the TNM classification. With the 8th edition, these patients are now all stage II and IIIA.
Dr. Florez: That’s so important to mention, especially with the 9th edition launching as well. As we talk about the design, and these agents are most likely to become a standard of care pending regulatory revision, what are some of the patients that you wouldn’t consider good candidates for alectinib in the adjuvant setting?
Dr. Solomon: It’s quite hard to think of a patient group who meets eligibility in terms of disease characteristics that I would not treat with alectinib. There are patients that tolerate it poorly because of issues like myalgias and CK elevations, but usually these are quite manageable with dose reductions. So I think, compared to the chemotherapy population, a lot more patients will be able to have alectinib. Again, I think if their resected disease is the new stage II and IIIA, I think those are the patients I’d discuss adjuvant alectinib with.
Dr. Florez: I think that’s a very important point. You mentioned that as a discussion. I think when I was talking to these younger women I mentioned earlier, it was a discussion. Something else we have to take into account is the financial toxicity of the drug. Unfortunately, the drug is expensive in the US. In many parts of the world, we don’t have universal health care, so it can be challenging. There are drug assistance programs, but I think that is evolving. Hopefully eventually, everybody will be able to get the drug regardless of the financial toxicity.
Dr. Solomon: Thank you for bringing that up. I think financial toxicity is a huge issue across the globe. Even in Australia, patients have to pay. If patients have adjuvant osimertinib, at the moment, they need to pay for it. That’s beyond the financial ability of most patients.
Dr. Florez: Yeah. I think that’s a good discussion for a future podcast. So, what is the future of targeted therapy, particularly in the ALK space in the neoadjuvant setting? As we know, there is a natural progression in life. Compounds in lung cancer have a similar natural history. With alectinib we saw second-line, first-line in the metastatic setting, and now the adjuvant setting. So, will the next stage in the natural history be in the neoadjuvant setting? What are your thoughts, Ben, about the future of ALK therapy in that space?
Dr. Solomon: You are absolutely right about the sequence of investigation, and there are studies with ALK inhibitors in the neoadjuvant setting. I think this will be interesting, and it is something that we will need more data to clarify. We’ve seen exciting data with neoadjuvant immunotherapy. There’s been a question about whether that will hold for targeted therapies. With neoadjuvant EGFR inhibitors, the pathological complete response rate has not been super impressive. It’s been very low. With neoadjuvant ALK inhibitors, we have limited data.
There is one study called NAUTIKA1 that we have data from nine patients, and there were three complete pathological responses. You could say a 33% complete pathological response rate, which is encouraging, so it might be that ALK inhibitors are different from EGFR inhibitors in the neoadjuvant setting, but I think we will need more data. I encourage people to continue to support these neoadjuvant studies because that is how we will learn.
In the adjuvant setting, as you’ve already raised, there are plenty of remaining questions: The role of chemotherapy? The optimal duration of therapy? And there are studies being planned to explore these questions. There’s also a study in locally advanced disease. We know the benefit of adjuvant durvalumab after chemoradiation, but we don’t know if that holds for oncogene-driven tumors, including ALK-rearranged lung cancer. There’s a study called HORIZON-01, which randomizes people with locally advanced ALK-positive non-small cell lung cancer treated with chemoradiation to alectinib or to durvalumab.
Dr. Florez: I am very excited about all these new treatment options. So Ben, thank you for answering all my questions. Is there any additional information that you would like to share with the audience?
Dr. Solomon: No. I’ve really enjoyed the conversation, and I think we’ve covered a lot of ground. As you say, it will be interesting and important to await updates from the ALINA study. There are several ongoing studies looking at how we can best treat resected early-stage lung cancer, but I think a message that I would like to get out is that we’re not very good. We’re much better at testing advanced disease for oncogene rearrangements than we have been, but now we’ve got compelling data to test early-stage disease for actionable oncogene targets, including EGFR and ALK and hopefully many others. I think my parting message would be to make sure that we test all resected and early-stage disease for EGFR, ALK, and ideally other oncogenic targets.
Dr. Florez: That’s a very important point. This is a great parting message, Ben, that biomarker testing is essential at all stages now. This has been a great discussion. Thanks, Ben, for your time and for all the work that you have done and continue to do to advance the field. Thank you for joining us.
Dr. Solomon: Thanks so much, Narjust. It’s been a real pleasure. Thank you.
