Focus of Next Treatment Era in ALK-Positive NSCLC Will Be Fusion Partners, Optimal Sequencing

Danielle Ternyila

Sai-Hong Ignatius Ou, MD, PhD,&nbsp;discusses the ALK inhibitors that are currently available for the treatment of <em>ALK</em>-positive NSCLC, as well as ongoing research in this space. He also sheds light on optimal sequencing strategies with these available agents.<br /> &nbsp;

Sai-Hong Ignatius Ou, MD, PhD

In the next era ofALK-positive non—small cell lung cancer (NSCLC) treatment, the focus will be on identifying fusion partners and determining optimal sequencing with the available agents, according to Sai-Hong Ignatius Ou, MD, PhD.

ALK inhibitors currently approved by the FDA include crizotinib (Xalkori), alectinib (Alecensa), and ceritinib (Zykadia) in the frontline setting, and brigatinib (Alunbrig), which Ou believes will also gain frontline FDA approval within the next year. Lorlatinib is also anticipated to be approved by the FDA by the end of this year for use after 1 or 2 prior lines of ALK inhibitors.

Several ongoing clinical trials are comparing second-generation ALK inhibitors to the first-generation ALK inhibitor crizotinib (Xalkori) in this patient population, but determining the best treatment options following second- and third-generation ALK inhibitors will be key, Ou says.

In an interview withTargeted Oncologyduring the at the 19th Annual International Lung Cancer Congress, Ou, a clinical professor at the University of California Irvine School of Medicine, discussed the ALK inhibitors that are currently available for the treatment ofALK-positive NSCLC, as well as ongoing research in this space. He also sheds light on optimal sequencing strategies with these available agents.

TARGETED ONCOLOGY:You gave a lecture on first- and next-generation ALK inhibitors. What were your main points in this talk?

Ou:My lecture is on crizotinib and next-generation ALK inhibitors. I [want] to emphasize what’s available and what’s being done in the second decade of the ALK-positive NSCLC treatment era. I would like to stress what we want to achieve in the next decade. One of them is a more precise diagnosis to know the fusion partners, because there are now very recent preclinical data from Dr. Alice T. Shaw, MD, PhD’s lab and Dr. Christine M. Lovly, MD, PhD’s lab in Vanderbilt.

One paper just came out showing that fusion partners affect the sensitivity to different ALK inhibitors. We need to know, not just by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC), but actually know the fusion partners. Number 2, we need to know the resistance mechanisms, whether it’s acquired resistance mutations or the bypass pathway.

To speculate what will be the future data — because all the second-generation ALK inhibitors are comparing to crizotinib – we expect every one of them to be positive. That’s a no brainer. The key is what to do if you started a second-generation, what to do as a subsequent treatment. If it’s a third-generation, what is the subsequent treatment? I present the data from the IMpower150 study that was presented by Dr. Mark A. Socinski, MD, at the AACR meeting, where carboplatin, paclitaxel (Abraxane), bevacizumab (avastin), and atezolizumab (Tecentriq) seemed to improve the PFS compared to chemotherapy alone inEGFR+ and [ALK+] NSCLC.

This may be an avenue in the future, to combine chemotherapy plus immunotherapy. A lot of the randomized phase III trials are still ongoing.

TARGETED ONCOLOGY:We recently saw a press release that brigatinib improved PFS in the frontline setting forALK+ NSCLC. Can you share your thoughts on this data?

Ou:I personally would think that brigatinib, in 1-2 years’ time when they actually have the PFS, it will be longer than alectinib. My feeling is that this is a very early data cut. We will probably not have the numbers for PFS for brigatinib [at World Lung], I think it will be not reached and not evaluable, so we are back to hazard ratio.

My feeling, though, is that it will be longer than the 25.7 months that was achieved by alectinib in the ALEX study, based on the independent review committee. My personal feeling is that brigatinib can achieve up to 33 months in PFS. That is my personal [opinion]. I don’t think we will know the data at World Lung, because I think it is still too early. The median PFS is likely not reached by brigatinib at this time. We will know in about a year’s time in a subsequent follow up. I still think it will be better than alectinib.

TARGETED ONCOLOGY:What is the role of crizotinib or ceritinib at this point?

Ou:Crizotinib, unfortunately, is probably not going to be more than a historical footnote in the very near future. I can see the only scenario where crizotinib would be useful is if lorlatinib is used upfront because it can overcome some of the resistance mutations to lorlatinib. That will be 5 years from now, at least, if lorlatinib becomes the frontline standard of care as a third-generation ALK inhibitor.

Ceritinib has a role. Ceritinib is a very potent ALK inhibitor. It has a role. It’s important to keep ceritinib in mind, especially if there is the FDA approval of 450 mg with food, which will be better tolerated. There are other ALK inhibitors that have a role too, but I don’t think they will play a major role.

TARGETED ONCOLOGY:For patients with CNS metastases, is there a specific sequence that you use?

Ou:Right now, alectinib and ceritinib are the only 2 second-generation ALK inhibitors approved by the FDA as a frontline treatment. I anticipate in the next year or so, brigatinib will also achieve the FDA approval as well. In that case, my feeling is brigatinib has better CNS data. I mention the ALTA-1L study. The updated publication in theJournal of Clinical Oncologyby D. Ross Camidge, MD, PhD, shows that the intracranial PFS was 18 months in the 90 mg-180 mg cohort. This is the longest intracranial PFS. This may be the go-to ALK inhibitor in the near future. We will wait for the readout for the lorlatinib versus crizotinib study, because lorlatinib is also designed to be one of the highest CNS-penetrant ALK inhibitors. It is also of the most potent ALK inhibitors currently available.

TARGETED ONCOLOGY:We are anticipating the FDA to approve lorlatinib soon. Overall, what do you think your optimal sequencing strategy will be once that agent is approved?

Ou:With the anticipated lorlatinib approval, I anticipate that lorlatinib will be used after 1 second-generation ALK inhibitor. There’s potential in the beginning that it will be after 2 second-generation ALK inhibitors as more clinicians get used to the side effects of lorlatinib, which are easily manageable if you know how to manage them. It’s not as bad as we heard in some of the discussions by the clinicians. I think there is some education to learn how to manage the side effects of lorlatinib. I think once clinicians are more accustomed to managing the side effects, it will probably be the second ALK inhibitor to be used at this point.

TARGETED ONCOLOGY:Is there anything you can say about resistance mechanisms?

Ou:There is a lot of bypass system mechanisms. One of them is small cell transformation, so it is very important to biopsy tissue and not just circulating DNA, especially if you suspect a patient to suddenly progress very rapidly. Small cell transformation has been reported, we have published a case report and a review of the literature on small cell transformation.

The other bypass pathway is Src activation, and also EMT, epithelial-mesenchymal transition. The Colorado group has published about EGFR activation, GIST activation, and, most recently, the MGH group has published on the SHIP2 activation, the phosphates to activate the RAS pathway. It’s very diverse and you really have to have tissue biopsy done to understand the bypass pathway. Liquid biopsies are good for acquired resistance mutations, but if you don’t detect a resistance mutation, you should biopsy the tissue. Also, always remember small cell transformation. It’s a potential resistance mechanism.

TARGETED ONCOLOGY:For a patient that progresses on multiple ALK inhibitors, what do you suggest for next treatment steps?

Ou:If a patient has progressed on multiple ALK inhibitors, my feeling is to continue chemotherapy and do the maximal cytoreduction. For a younger patient, I would use carboplatin and pemetrexed, and if the brain metastases are controlled, add bevacizumab in, too. Then, use the other regimen of carboplatin, pemetrexed, and bevacizumab, followed by pemetrexed and bevacizumab maintenance. I would also use a continued highly CNS penetrant ALK inhibitor. I’ve used alectinib and brigatinib. I’m currently treating some patients who have progressed on 1 first-generation, 2 second-generation, and 1 third-generation ALK inhibitor and now have to do chemotherapy. I will also put them back on a second-generation ALK inhibitor that has good CNS penetration. You have to do both. It’s not what is recommended; it’s not in any guidelines, but since the ALK inhibitors are so well tolerated and there is no cross-toxicity, I do use chemotherapy plus ALK inhibitors.

You don’t have to use the chemotherapy for a long time. You can achieve maximal cytokine reduction and just continue ALK inhibitors, then restart the chemotherapy if they progress again. Chemotherapy doesn’t care if you haveALKmutations orEGFRmutations, or other things in order to kill the cells. They don’t discriminate against driver mutations.