Reviewing OPAL Results in EGFR+ NSCLC Before Phase 3 FLAURA2 Presentation

Martin F. Dietrich, MD, PhD

TARGETED ONCOLOGY: What data support the use of osimertinib (Tagrisso) plus chemotherapy as first-line treatment for EGFR-mutated non-small cell lung cancer?

DIETRICH: The OPAL trial [jRCTs031180226] regimen…is something we’ll see [more data on] at the World Conference on Lung Cancer [WCLC] coming up in September. We’ll see the FLAURA2 study [NCT04035486], which is investigating the combination of chemotherapy plus osimertinib for EGFR-mutated disease upfront, looking at osimertinib plus carboplatin/pemetrexed with pemetrexed maintenance in this setting.

The OPAL study was a phase 2 study that looked at both cisplatin and carboplatin arms of treatment, something that we wouldn’t necessarily do in the United States. [OPAL investigators were] looking at a fairly high-risk population, about a third with brain metastases at baseline. I think it’s an interesting study.

The question is, are we going make a meaningful impact? The OPAL [data] would certainly suggest that we do. How much is enough? Who are the patients that are eligible for chemotherapy? I think this is going to be an interesting contender to replace first-line standard of care.

What were the efficacy outcomes of the OPAL trial?

In terms of overall survival [OS], the carboplatin arm performed a bit better [2-year OS rate, 97.0% (95% CI, 80.4%-99.6%) vs 87.5% (95% CI, 70.0%-95.1%) with cisplatin; median OS not reached in both arms].¹ I’m not sure if this is, in a nonrandomized setting, a biased assessment in terms of how our patients are doing, but I think what’s clear from the study design is that the median progression-free survival [PFS] and the OS that we’re seeing look quite competitive. When we are looking at the PFS, we’re looking at a median of 31.0 months [95% CI, 26.8­–not reached].

The median OS for FLAURA [NCT02296125] was 39 months [at 35.8 months median follow-up],² and we’re certainly far above that [median OS not reached at 33.4 months median follow-up (range, 30.2-37.7) in OPAL].¹ This small study is phase 2 and nonrandomized, but is certainly looking competitive for this treatment. We’ll see how this is going to shake out; [it is] probably one of the most awaited data pieces coming at WCLC in September in Singapore. But we’re looking forward to how this is going to be implemented. There are 2 schools of thought on whether the sequence is going to be better [than FLAURA]. There will be many who say we want to see OS [from FLAURA2]. But I think if the result of the FLAURA2 study [is similar to OPAL], we will see about a year of additional PFS that certainly becomes tempting for young, fit patients.

What do the subgroup analyses of OPAL indicate about treating patients with EGFR mutated-disease?

Looking at the subgroups, the 1 that’s of interest is EGFR exon 19, [which] has always done better than EGFR exon 21. Very interestingly, it’s not that big of a difference between EGFR exon 19 and exon 21. Maybe the upfront cytoreduction of resistant clones with EGFR exon 21 is helpful.

I think that we’ll see a very finely dissected subgroup analysis of FLAURA2 to see, aside from assessing the patients for chemotherapy eligibility, whether there are molecular markers that would drive us to select 1 combination over the other. My prediction would be that especially for those with EGFR exon 21, this will become a very interesting area. [It may be that] the OS benefit here was driven largely by exon 19. I think exon 21 will be high on the list of suspicions, but that’s an interesting sneak preview of what’s going to come in September.

OS is still difficult to interpret. I don’t know what to make of it. Those OS information pieces, whether it’s [with] cisplatin or carboplatin, are simply too early [with the patient] numbers too small to [interpret], but it is provocative to look at an OS rate of approximately [over] 80% at 36 months. It would be practice changing, in my opinion. If you have a PFS benefit of a year, it’s hard to see how that wouldn’t translate into OS. But it’s always good to have that additional option. [Adding chemotherapy] would also solve the turnaround time if you think about it. We’ll see what the [phase 3] data show.

_References:

_{1. Saito R, Sugawara S, Ko R, et al. Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study. Eur J Cancer. 2023;185:83-93. doi:10.1016/j.ejca.2023.02.023}

_{2. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662}