Konstantinos Arnaoutakis, MD, discusses pivotal updates in stage III disease, immunotherapy combinations in advanced non–small cell lung cancer, and advances in EGFR- and ALK-mutated lung cancer.
Konstantinos Arnaoutakis, MD
There has been a heavy focus on individualization in lung cancer treatment over the last 10 years, explained Konstantinos Arnaoutakis, MD, touting advances with immunotherapy as well as targeted therapies for patients with EGFR- and ALK-positive disease.
“It is not one disease anymore. It’s not about histology; it’s not even about [one] genetic abnormality,” said Arnaoutakis. “All of these genetic abnormalities we have seen are so dynamic because they change over a period of time, partly because of the intratumoral heterogeneity but also the intertumoral heterogeneity. We will see more sequencing data that will allow patients who progress to receive the appropriate treatment.”
In an interview during the 2019 OncLive® State of the Science SummitTM on Non—Small Cell Lung Cancer, Arnaoutakis, a hematologist and oncologist, associate professor in the Department of Internal Medicine, Division of Hematology and Oncology, the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences, discussed pivotal updates in stage III disease, immunotherapy combinations in advanced NSCLC, and advances in EGFR- and ALK-mutated lung cancer.
OncLive: Could you share the data with the PACIFIC trial in patients with unresectable stage III NSCLC?
Arnaoutakis: The [PACIFIC trial] was a study that randomized patients to durvalumab (Imfinzi) or placebo after chemoradiation therapy. We are very excited because we haven’t had any major improvements in survival for stage III locally advanced NSCLC in the past. Now we do, and we get more information about things in the past that were concerning to clinicians—with regards to things like pneumonitis. [We are looking at] other things [to tweak] the treatment, such as how quickly someone should start immunotherapy upon completion of chemoradiation and things like that. Still, [who] the optimal candidates are is still a concern for many clinicians, so that’s kind of an important topic, despite the data that have already been presented.
Is there a rationale to explore other checkpoint inhibitors in this setting?
That is a good question; it’s kind of difficult to say. On one hand, immunotherapy agents are all the same, but in reality they are not. Pharmacologically, many of these are different antibodies with different affinities, and it does make sense to try different immunotherapy agents. The problem, though, is clinical trial design, and some patients may be concerned about trying a different immunotherapy than the standard of care, which right now is durvalumab.
How would you describe the impact of durvalumab in this setting?
In many ways, it has changed the landscape because it was the proof of principle that an immunotherapy agent can alter the course of this disease and improve survival. There are still clinicians who are still concerned about the adverse event (AE) profile, and sometimes they may elect to use an immunotherapy agent upon progression to avoid potential AEs, although that has not been fully supported by the data.
The impact has been significant and we’ll see more [immunotherapy developments] even in earlier-stage disease, such as stage I or II in the neoadjuvant setting. Selecting candidates is going to be an issue with regards to the clinical characteristics. We are already getting some information from a subgroup analysis of PACIFIC, but also with biomarkers that apply to all stages. That will be a great thing, which I look forward to in the future.
There have been updates with immunotherapy in the first-line setting, specifically with immunotherapy and chemotherapy combinations. Could you discuss these data?
For a while, we were concerned about what to do with patients who have low PD-L1 expression, and we had exciting data about monotherapy in patients with PD-L1 expression more than 50%. With combination chemotherapy and immunotherapy, we were happy to see improvements in survival for patients with low PD-L1 expression.
There are so many studies that are in the pipeline right now and some of them we are eagerly waiting for the results for—some of the IMpower studies, for example. Some of them might lead to an approval for a new agent, and some of them we are still waiting for survival results. We are still excited about finding ways to avoid chemotherapy if possible, and hopefully the future will give us some subgroup of patients who have a biomarker that can avoid chemotherapy for those patients.
Could you discuss the benefit seen in the IMpower150 trial with atezolizumab (Tecentriq), bevacizumab (Avastin), and chemotherapy in patients with EGFR-mutant NSCLC?
In IMpower150, there was initially a trend in EGFR-mutation—positive patients and the data that were reported have shown a survival benefit for that relatively small group of patients. I’m not sure if the study was designed [to explore that population] from the beginning, so studying them in the future might also be an important study to do for that group of patents.
Transitioning into EGFR-mutant NSCLC, what agents have demonstrated exciting activity?
EGFR is the “poster child” of targeted therapies in lung cancer; we are very excited to see things improving and progressing. The exciting thing is osimertinib (Tagrisso) in the first-line setting; there is a lot of excitement about how to individualize and tailor therapies in patients who progress on osimertinib. There are still no mature data, but there is a lot of excitement about the sophistication of technology that allows patients with individual mutations to get the appropriate treatment. That is, of course, something that we eagerly expect in the future, but there was a presentation at the 2019 ASCO Annual Meeting for patients who progress on osimertinib with a different acquired resistance mutation.
Could the combination strategies being evaluated with osimertinib hold ground?
A lot of people tried different things to optimize the effect of first-line therapy with osimertinib in combination with other agents—for example, with angiogenesis drugs. A phase I study that is being designed was presented at the 2019 ASCO Annual Meeting with bevacizumab and osimertinib. But, there is also excitement about how to improve the survival in patients who progress on osimertinib with the addition of other agents. Right now, there are a lot of studies out there that are combining osimertinib with other things, but nothing is very [far along] at this point.
The RELAY trial evaluated the combination of erlotinib (Tarceva) with ramucirumab (Cyramza) in EGFR-mutant patients. What is the importance of this study?
That was also quite exciting. The RELAY study is a phase III study [evaluating the combination of] erlotinib and ramucirumab, which is a monoclonal antibody against VEGF. In the first-line setting, results showed some improvement in PFS in the combination arm. The PFS was very similar to osimertinib in the FLAURA study; however, there is still not a survival benefit and there is still a different AE profile because of the angiogenesis drug. This is a study that is significant because it kind of, again, has the proof of principle that antiangiogenesis has a role in the EGFR-mutant patients, but it is difficult to say that it’s ready to replace osimertinib right now as a first-line therapy.
How is dacomitinib (Vizimpro) being utilized for patients with EGFR-mutant NSCLC?
The phase III ARCHER 1050 study [looked at] dacomitinib versus gefitinib and showed a survival benefit in the experimental arm. It also led to the approval of dacomitinib in that patient population [for first-line therapy]. It has a different side effect profile; these are always a concern for new drugs, especially ones that we don’t use very often. However, the FLAURA study also makes things a little more complicated, because [the FLAURA data] are another reason for people to avoid the usage of dacomitinib right now.
Finally, could you speak to the management of patients with ALK- and ROS1-positive NSCLC?
ALK has also been able to keep up with the EGFR story, and we now have several drugs that are approved. We have first-, second-, and third-generational ALK inhibitors. We are very excited with the lorlatinib (Lorbrena) data, which led to the approval of lorlatinib in the second-line setting.
The excitement comes down to the fact that these third-generation drugs penetrate the central nervous system (CNS) barrier, so we see very exciting data in response rates and a PFS benefit in the CNS. It is exciting because all of these drugs work in slightly different ways; they target different ALK resistance mutations.
ROS1 is a more infrequent genetic alteration, so studies have always suffered from [low] enrollment. The approval of crizotinib (Xalkori) in ROS1-positive patients was based on a study that had 40 or 50 patients, and then we got data for ceritinib (Zykadia) and lorlatinib. Although these drugs are not approved in ROS1-positive NSCLC, they are [included] in the National Comprehensive Cancer Network guidelines.
Is this a space that is becoming more difficult to determine the optimal sequence of therapies?
Yes, but that is why clinical trials are important to happen. There is a plethora of drugs and some of them might never be compared with one another, but the story lately has shown that a group of experts in this group of diseases—EGFR and ALK—has allowed these drugs to be used in a way that gives me excitement—that the sequencing in the future will happen in a much more sophisticated and intelligent way.
What research is being done at your institution that you would like to highlight?
We have an interest in vaccines, and we have been using a carbohydrate peptide mimotope, which is a new vaccine—a homegrown product at the University of Arkansas for Medical Sciences—that we are combining with immunotherapy. There is a lot of interest for combination immunotherapy studies either through checkpoint inhibitors or vaccines. In the past, vaccines haven’t been so successful, but in combination with immunotherapy, it is possible that it may have better results.