Navigating the Complex Paradigm of Oncogene-Driven NSCLC

Lara Kujtan, MD

Based on recent data, there are well-defined frontline options for patients with non¬—small cell lung cancer (NSCLC) who harbor EGFR or ALK mutations, as well as rarer drivers such as ROS1 and BRAF. However, more data are needed to understand how to best sequence these therapies, said Lara Kujtan, MD.

In the EGFR space, osimertinib (Tagrisso), a third-generation TKI, seems to be the optimal frontline agent based on positive data from the phase III FLAURA trial. In the study, osimertinib reduced the risk of progression or death by 54% compared with standard TKI therapy options erlotinib (Tarceva) or gefitinib (Iressa). The median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) with standard therapy and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001). Meanwhile, the median overall survival (OS) was not yet reached.

For ALK-positive NSCLC treatment, alectinib (Alecensa) has been identified as standard frontline therapy following its November 2017 FDA approval. Although brigatinib (Alunbrig) has shown recent promise, there are not enough data to support replacing alectinib in the frontline setting. In November 2018, lorlatinib (Lorbrena) became the most recent ALK inhibitor to be approved by the FDA for second-line treatment following progression on 1 or more ALK TKIs.

Another breakthrough was the November 2018 FDA approval for larotrectinib (Vitrakvi) for the treatment of adult and pediatric patients with solid tumors with an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity. NTRK is rarely expressed in NSCLC, but this is an effective option for the small patient subset.

OncLive: What is the optimal frontline option for EGFR-positive NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Kujtan, an assistant professor at the University of Missouri–Kansas City School of Medicine, shed light on how to navigate the complex paradigm of oncogene-driven NSCLC and stressed the importance of patient preferences when deciding on optimal treatment approaches.Kujtan: Based on the FLAURA study, I would argue that [osimertinib] is what we should use in the frontline setting for our patients for different reasons. There is improved PFS [with this TKI], but the OS data are not mature yet from this study. There is also central nervous system (CNS) activity with osimertinib. In the ARCHER 1050 study, which looked at the use of dacomitinib (Vizimpro), a second-generation EGFR TKI, compared with other common regimens such as erlotinib and bevacizumab (Avastin) or gefitinib and chemotherapy. We [learned that] these drugs can improve survival, but we don't see a benefit in terms of CNS activity.

What advances have been made in the frontline treatment for patients with ALK-positive NSCLC?

What are the available agents for patients who harbor the rarer mutations?

The FLAURA study compared the use of third-generation EGFR TKIs with first-generation EGFR TKIs. Patients were randomized to receive either osimertinib or gefitinib/erlotinib. The primary endpoint was PFS; the trial met its primary endpoint with a statistically significant increase in PFS at 18 months with osimertinib versus 10 months in the control arm. It was essentially almost a doubling in PFS. Interestingly, they also did several subgroup analyses, and every one of them showed favorable advantage for osimertinib. This was especially the case for CNS metastases, which is not something we had previously seen.We have 4 agents approved in the frontline setting for ALK-driven disease. The National Comprehensive Cancer Network guidelines still have alectinib as the preferred agent, but recently, we have seen encouraging data with brigatinib. We still need longer-term data for brigatinib before we can compare the PFS and CNS activity [with the preferred agent]. This is something we will be eagerly awaiting.In patients with BRAF mutations, there have been some recent trials with single-agent vemurafenib (Zelboraf) that unfortunately seem to show a lot of toxicity for patients. Combination therapies with dabrafenib (Tafinlar) and trametinib (Mekinist) seem to be the best that we have so far.

What other emerging treatment targets are under investigation?

What are the factors that should be taken into consideration when choosing the optimal sequence?

What are some questions that still need to be addressed?

Is there anything you would like to add?

For ROS1-mutated NSCLC, we actually have several agents that are currently being studied. [For example,] crizotinib (Xalkori) is a drug that has potential in some of these rarer driver mutations. [In my presentation], I also discussed some of the newer NTRK inhibitors, such as entrectinib. A lot of the data with these are early phase I data, so it’s too soon [for their use] to be implemented in practice. However, there is a lot of ongoing work.There is a litany of new targets. You name it and there is something out there. HER2 is something that is being looked at, and NTRK, as we mentioned earlier, is a bit of a hot topic right now—especially with the recent FDA approval of larotrectinib for all solid tumors. This has generated a lot of interest.There are many different things you want to look at, and all of them are going to be personalized to your patient. That is the whole drive behind looking at these oncogenic drivers and mutations. We have effective therapies to target them, but you want to think about the patient in ways aside from their molecular profile. For example, what types of toxicities do these agents have? Do they have CNS disease?We need to know more about how to sequence these therapies. We don't have a lot of data yet regarding that. The other thing we need to find out is in terms of mechanisms of resistance. While these drugs are working, these patients are still eventually developing resistance.In my presentation, I also discussed a trial presented at the 2018 World Lung Conference. It was an interesting trial because they were looking at patient preferences. They were all patients with EGFR-positive disease and they were asked to fill out a survey of a hypothetical scenario. If they were able to choose between drug “A” and drug “B,” which would they choose? For example, drug “A” had incredible PFS, but horrible side effects. [Conversely], drug B had not-so-great PFS but excellent side effects. When patients were shown those comparisons, the results were 50/50.

Some people value increased longevity, while others value less adverse events. This brings up the importance of having these conversations with your patients and determining their preferences. They should have a huge input in the decision-making process.

Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non—Small-Cell Lung Cancer. New Eng J Med. 2018;378:113-125. doi: 10.1056/NEJMoa1713137.