Shum Sheds Light on Oncogene-Driven NSCLC Treatment Options

Elaine Shum, MD

Following frontline TKI approvals, researchers are still trying to determine the role of older-generation TKIs in the treatment of patients with oncogene-driven non—small cell lung cancer (NSCLC), as well as ways to overcome acquired resistance to these agents, said Elaine Shum, MD.

Osimertinib (Tagrisso), a third-generation EGFR TKI, gained FDA approval in the frontline setting in April 2018 for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations). The decision was based on data from the phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus first-generation TKIs erlotinib (Tarceva) or gefitinib (Iressa). The median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for 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). Overall survival (OS) data have not yet been published.

For ALK-positive NSCLC treatment, alectinib (Alecensa) has been identified as standard frontline therapy following its November 2017 FDA approval. In November 2018, lorlatinib (Lorbrena) became the most recent ALK inhibitor to be approved for second-line treatment following progression on 1 or more ALK TKIs.

OncLive: What are the updates in frontline options for patients with oncogene-driven NSCLC?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Shum, a medical oncologist at NYU Langone’s Perlmutter Cancer Center, discussed the rapidly evolving treatment options for patients with oncogene-driven NSCLC.Shum: It has been a very exciting past couple of years in terms of new FDA approvals for drugs in the frontline setting. In my presentation [at the State of the Science SummitTM], I focused on ALK- and EGFR-[targeted therapies], and I also touched on some of the rarer oncogenic drivers.

In EGFR-mutated NSCLC, osimertinib is approved in the frontline setting. What are some unanswered questions with this drug?

What are your thoughts on the use of dacomitinib (Vizimpro) in the EGFR space?

What is the optimal frontline agent for ALK-driven NSCLC?

In what patients would you use an earlier-generation TKI?

What are some ways to overcome resistance to these therapies?

How important is next-generation sequencing (NGS) testing?

What are other emerging biomarkers in NSCLC?

ALK and EGFR, specifically, have seen some significant additions to the landscape. For example, I discussed the FLAURA data, which everyone has become familiar with. In the ALK space, the 19th Annual World Conference on Lung Cancer showed us some big data with brigatinib (Alunbrig); it is important to understand how this affects alectinib. In ROS1-driven disease, we still have our trusted agent crizotinib (Xalkori).The data from FLAURA were very impressive and led to the FDA approval in the frontline setting. We are definitely already using this in practice. One thing we still don't have are OS data; however, we saw a significant PFS benefit with this drug, so I don't think any surprising OS data are going to change the way we use osimertinib. The effect on central nervous system penetration we are seeing with osimertinib is really what takes it beyond the other EGFR inhibitors.Dacomitinib had very impressive data in the ARCHER 1050 study, but the toxicity profile gives us reason for concern. There is much stronger toxicity than what we are used to seeing with EGFR TKIs, especially with osimertinib being a generally well-tolerated drug. For me, personally, I don't think I'll be using dacomitinib simply based on the toxicity. However, as we learn more about sequencing these EGFR TKIs, dacomitinib could have a role. In other parts of the world, dacomitinib could be the right choice.Based on the ALEX study, alectinib should be what we use in that setting. Brigatinib has certainly been an effective drug, but we obviously don't have a head-to-head comparison between the 2 agents. For now, alectinib would be my choice.[I would use these agents] in patients with uncommon EGFR mutations like G719X. These mutations are found in a very small percentage of patients, but they are there. For these patients, I wouldn't be rushing to use osimertinib upfront. Afatinib (Gilotrif) has been approved for use in these uncommon patient populations.It is a very good question, and we are still learning why tumors develop mechanisms of resistance. We don't know enough yet about why this happens, but it seems that the targeted agents we're using select out a clone and allow another clone to drive the disease and go undetected. More studies involving more biopsies at the time of progression can help us answer this. There is potential for us to use different TKIs in combination but toxicity becomes a concern. There are some anecdotal studies of EGFR-mutant patients with MET amplification, and they had improved outcomes with an EGFR inhibitor and MET inhibitor.It is pretty obvious that every patient at diagnosis, especially with stage IV disease, should undergo NGS testing. We are finding new oncogenic drivers based on these NGS tests and it is helping us gear treatment in a more personalized way. As NGS becomes more accessible and affordable, it will become the standard and help us improve patient outcomes.It is important for us to understand the much less common, but definitely present, oncogenic drivers, such as RET and MET. These drivers appear in around 1% to 2% of patients with NSCLC but identifying them can make a difference for your patients because there are options available. Tumor mutational burden also seems to be an effective biomarker in terms of immunotherapy response.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. In: Proceedings from the 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/Osimertinib-vs-standard-of-care-SoC-EGFR-TKI-as-first-line-therapy-in-patients-pts-with-EGFRm-advanced-NSCLC-FLAURA.