Based on the favorable efficacy results of the randomized phase 3 FLAURA trial that compared the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib to either first generation EGFR TKI gefitinib or erlotinib,1 osimertinib is the preferred first line treatment per clinical guidelines from National Comprehensive Cancer Network (NCCN)2 and the European Society for Medical Oncology (ESMO)3 and is broadly favored as the leading option where it is available. The leading challenge with this agent is its high cost of more than $15,000 per month in the US, which can lead to difficulties for patients to whom it is prescribed but who struggle with copays or lack of insurance. In many parts of the world, including some with high proportions of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), osimertinib is not available due to its cost. When cancer therapies are inaccessible due to their cost, they provide no benefit.
It is in this setting that the third-generation EGFR TKI aumolertinib is being developed. Apart from being enrolled and conducted entirely in China, aumolertinib has been studied in the AENEAS trial, which echoes the design of FLAURA. Specifically, the trial pursued a 1:1 randomization of 429 Chinese patients with advanced, systemic therapy-naïve EGFR mutation-positive NSCLC to aumolertinib or gefitinib once daily, with a primary endpoint of progression-free survival per investigator assessment.4 Notably, patients with evidence of EGFR T790M mutation-acquired resistance upon repeat biopsy after progression were eligible to crossover to aumolertinib, as was the case for osimertinib in the FLAURA trial.
The results available thus far largely recapitulate the results of FLAURA, with a significantly longer PFS in recipients of aumolertinib versus gefitinib (median PFS 19.3 vs. 9.9 months, respectively) despite similar objective response rates (ORRs) for aumolertinib and gefitinib (73.8 vs. 72.1%, respectively). Importantly for a therapy intended to be taken longitudinally, rash and diarrhea (any grade) were lower with aumolertinib than with gefitinib (23.4 and 16.4%, respectively with aumolertinib, compared to 41.4% and 35.8% with gefitinib), though the rates of grade >3 adverse events (any cause) were similar, at 36.4% and 35.8% for aumolertinib vs. gefitinib, respectively.
With these results, AENEAS is clearly a positive trial, but of unclear clinical significance. While the original publication of FLAURA1 preceded the subsequently demonstrated improvement in overall survival (OS) seen with first-line osimertinib,5 the current strong preference for osimertinib in the US and elsewhere is predicated on a strong improvement in PFS and OS, a favorable, if not clearly superior, toxicity profile for osimertinib on the ADAURA trial, as well as compelling evidence that osimertinib confers far superior control against progression within the central nervous system (CNS) than first generation EGFR TKIs.6
In this regard, the AENEAS trial mirrors the FLAURA trial; it yields a very similar pattern of early results favoring aumolertinib with some suggestion of a marginally more favorable toxicity profile, but we do not yet have results for OS or CNS activity that have already elevated osimertinib to an optimal strategy where available.
While aumolertinib is approved for use in China and reimbursed nationwide, the pricing strategy of osimertinib in China is different from the rest of world. Facing competition with aumolertinib in China, osimertinib has now been offered at a price that is low enough to maintain its coverage and reimbursement in China. By providing reasonable and affordable pricing for both aumolertinib and osimertinib, third generation EGFR TKIs become more available for routine clinical use, which, in turn, translates into improvements in lung cancer outcomes. This can serve as a possible model for how increased competition among third generation EGFR TKIs can lead to greater access to these agents.
In the parts of the world in which osimertinib is readily available, any incremental benefit of aumolertinib must be anticipated to hinge on a dramatic reduction in cost compared to osimertinib. Moreover, at the present time, the demonstrated OS benefit and efficacy of osimertinib in the CNS are features that have yet to be confirmed with aumolertinib, even if the early data with aumolertinib appear quite comparable to those observed with osimertinib.
To even consider changing practice, oncologists in the US and likely other parts of the world in which osimertinib is entrenched as a first-line standard of care would need to see similar data for aumolertinib accompanied by a dramatically lower cost. Even then, some may be inclined to change their choice of first line EGFR TKI only based on direction from payers or guidelines prioritizing value-based decisions; and many, if not most, may be uncomfortable changing therapies before confirming that aumolertinib can replicate the OS benefit and CNS efficacy over first-generation EGFR TKIs that is so valued with osimertinib.
The other critical question is whether the US Food and Drug Administration will be receptive to an application for aumolertinib based on a trial that enrolled patients exclusively in China and was designed around a primary endpoint of PFS, without reporting OS. This was largely the pattern for the recent application for FDA approval of sintilimab, another agent studied entirely in China. The FDA’s Oncology Drug Advisory Committee7 recommended against approving the sintilimab application since this agent largely replicated data generated by previously approved checkpoint inhibitors in the US; consequently, the FDA denied approval. However, historically, in other instances, the FDA has accepted PFS as an acceptable endpoint for targeted therapies, and aumolertinib represents only the second of the third generation EGFR TKIs.
Finally, it is notable that we have not seen discordant results between Asian and non-Asian populations in trials of targeted therapies for lung cancer, so we can have some confidence that delivering a targeted therapy for an appropriately molecularly selected population has been an equalizer across populations. That being said, FDA made a strong declaration in its sintilimab decision that price considerations would not open doors otherwise closed—consistent with their established policy of not considering drug cost for potential approval.
For agents like aumolertinib, which appear to demonstrate efficacy and tolerability comparable to established, FDA-approved options, we can appreciate a meaningful benefit of markedly lower cost, but these agents must navigate the gauntlet of FDA approval that will not consider anticipated or demonstrated cost as a factor. Based on agency’s decision regarding sintilimab, questions of pharmacokinetic differences between an exclusively Chinese trial population and a broader population in the US will prove to be a sticking point, particularly when combined with a suboptimal endpoint of PFS when the current standard of care yields proven superiority in OS.
While oncologists may well hold out for both OS results and demonstrated strong efficacy of aumolertinib in the CNS to ensure that it is truly comparable to osimertinib, it remains to be seen whether US-based oncologists will be motivated based on a significantly lower cost. Before US-based oncologists are even offered this consideration, however, we will need to determine whether aumolertinib can navigate through the channels on which sintilimab ran aground.
- 1. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. New Engl J Med 378: 113-125, 2018.
- 2. National Comprehensive Cancer Network (NCCN) Clinical Guidelines in Non-Small Cell Lung Cancer (version 1.2022). Website: bit.ly/NCCNNSCLC, accessed 3/16/2022.
- 3. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Accessed 3/16/2022.
- 4. Lu S, Dong X, Jian H, et al. Randomized phase III trial of aumolertinib (HS-10296, Au) versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer 9NSCLC) and EGFR exon 19 del or L858R mutations. J Clin Oncol 39 (#15, suppl), A#9013, 2021.
- 5. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382: 41-50, 2020.
- 6. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol 36: 3290-3297, 2018.
- 7. BLA 761222 ODAC: Sintilimab BLA in non-squamous NSCLC. Website: fda.gov/156090/download, accessed 3/16/2022.