Pennell Considers Treatments in Front- and Later-Line Settings for EGFR+ NSCLC

Nathan Pennell, MD, PhD

In the treatment of EGFR-mutant non–small cell lung cancer, oncologists face multiple challenges with prescribing medications to patients. During a Targeted Oncology Case Based Peer Perspective event, Nathan Pennell, MD, PhD, a Hematologist and Medical Oncologist, Cleveland Clinic in Cleveland, OH, discussed these challenges as well as potential treatment approaches with a group of peers.

Targeted Oncology™: What are your thoughts on this poll?

PENNELL: I would be [surprised] if anyone had 21 patients or [more]. Most people have [fewer] than that, which makes perfect sense.

What is the National Comprehensive Cancer Network (NCCN) recommended regimen here?

Osimertinib [Tagrisso] stands out as the preferred regimen based upon the FLAURA trial [NCT02296125].¹ But there [is] a whole list of approved drugs, including erlotinib [Tarceva], gefitinib [Iressa], afatinib [Gilotrif], and dacomitinib [Vizimpro], which is also a second-generation tyrosine kinase inhibitor [TKI]. I’m not sure I know anyone [who] has used [dacomitinib] other than on the trial. [We also have] ramucirumab [Cyramza] approved.

Have you had a similar experience to what physicians said in this poll?

I personally have found that prescribing osimertinib and other expensive new drugs [such as] alectinib [Alecensa], for example, seems to be getting harder.

Some people say they have no barriers. Worrying about cost [for] the patient and insurance coverage seems to be the other major [issues]. But I have not yet had a patient not be able to get a drug. It’s just taking longer sometimes to get them covered.

What are the data from the FLAURA trial that support its use in this setting?

These were patients with EGFR mutations.² They were allowed to have stable brain metastases on the study, but only exon 19 and 21 mutations, and they were randomly assigned first line to osimertinib or the first-generation TKI of either erlotinib or gefitinib. The primary end point was progression-free survival [PFS].

This study showed a big difference in PFS with a median of 18.9 months [with osimertinib] and 10.0 months with first-generation TKI [HR, 0.46; 95% CI, 0.37-0.57; P < .0001].

More importantly, there was a difference in overall survival [OS] presented in 2019 at the European Society for Medical Oncology Annual Congress supporting these.^{3 [}Osimertinib was a] good comparator to the first-generation TKI with a hazard ratio of 0.63 [in the original follow-up]2, and [it] is still [impressive] that the median OS for these patients was 38.6 months [vs 31.8 months with the first-generation drug].3 Half of the patients lived longer than 3 years in the first line with osimertinib. The hazard ratio was 0.79 [95% CI, 0.641-0.997].

There is an argument...that maybe we should be [using] first-line first-generation or second-generation inhibitors, and then, when patients progressed, you can test them and see whether they’re T790M positive. [If so], they can go on to osimertinib— wouldn’t that last longer? And then you have an option for your patients after they progress, but I wouldn’t stipulate that this trial tested that.

There were 47% of people in the standard-of-care arm [who] were tested and crossed over to osimertinib. That is about what you would expect. Despite that, there was a significant OS benefit. I think this tested [the different] sequencing and failed as a strategy.

Were there any other factors that influenced your use of osimertinib?

It’s clear that osimertinib works in brain metastases; it even works for leptomeningeal disease. So if you have a patient with leptomeningeal disease who is EGFR positive, you can treat these patients with osimertinib and see good responses, even at the normal standard dose. The adverse effects of the third-generation inhibitors are much less than what you see with the second-generation drugs [such as] dacomitinib and afatinib.

There is almost no rash with osimertinib, a bit of diarrhea, but it’s well tolerated. That is also a differentiating factor for me.

Is there a reason you might use a combination drug versus osimertinib? What data support that?

There are a lot of data suggesting that combining antiangiogenics with TKIs, especially the first-generation TKIs, does improve PFS. The RELAY trial [NCT02411448] led to the approval with improvement in PFS with the combination of ramucirumab and erlotinib, compared [with] erlotinib alone.⁴

PFS has been improved, but up to this point OS has not. In the combination of TKIs and VEGFs—that’s both with bevacizumab [Avastin] and with ramucirumab—in meta-analysis, no difference in OS was seen, but broadly they do seem to improve PFS.

It did show a big difference in PFS, with a median PFS of 19.4 months versus 12.4 months, so this is a similar magnitude of difference in what was seen in the FLAURA study. There was a hazard ratio of 0.59 [95% CI, 0.46-0.76; P < .0001]. There [were] no OS data presented on this. Presumably, [the data were] not mature.

There was more grade 1 bleeding seen with ramucirumab, but little grade 3 or 4 bleeding. There was clearly more hypertension in the ramucirumab group.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 6.2020. Accessed September 17, 2020. https://bit.ly/2EAH60w}

_{2. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113- 125. doi:10.1056/NEJMoa1713137}

_{3. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis. Ann Oncol. 2019;30(suppl 5):567. doi:10.1093/annonc/mdz394.076}

_{4. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5}