First-line Osimertinib for EGFR-Mutated Advanced NSCLC: Barriers to Access and Future Directions

In the treatment of non-small-cell lung cancer (NSCLC), a diverse disease with a variety of optimal treatment approaches, the best drug for each particular patient should be given upfront. For a patient with EGFR‑mutated NSCLC, the third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib has emerged as the optimal first-line treatment option based on a survival benefit demonstrated in the phase III FLAURA trial as compared with the first-generation EGFR TKIs, which you can read more about in this companion commentary. FLAURA is the first randomized phase III study to show an overall survival benefit compared with the first-generation EGFR TKIs—a benefit that was seen regardless of patient subgroup, although was notably less marked for Asian patients and those with an EGFR L858R mutation. Osimertinib also has an impressive safety profile and improved central nervous system penetration, which is important because up to 25% and 45% of patients will have brain metastases at diagnosis or will develop them during the course of their disease, respectively, and controlling or avoiding brain metastasis is very important to the quality of life of these patients. Despite osimertinib currently being the best first-line option for our patients with EGFR-mutated NSCLC, it is unfortunately not universally available and there are disparities in access across the globe.

Barriers to Osimertinib Access
Access to osimertinib and whether the cost of this treatment will be reimbursed varies by country and is influenced by the price of the drug and whether the FLAURA data have been fully embraced. Concerns about the cost of osimertinib therapy partly stem from the fact that patients who receive this therapy will do so until disease progression. Therefore, at the start of treatment, we do not know how long a patient will be on the drug. In the FLAURA trial, the median duration of exposure with osimertinib was 20.7 months, with a range of 0.1-49.8 months, so up to 4 years or even longer, which becomes very expensive. There are expanded access programs in some regions to help pay for treatment, but with this price tag, access to first-line osimertinib is going to come down to whether a country has approved its reimbursement or not. Osimertinib is a L858R or ex19del mutationEGFR very effective drug in the setting of an , and we do not want a situation where a patient ends up stopping treatment early because of the cost of the drug.

Some countries such as France, where I practice, and the United States and Spain are confident in the magnitude of benefit seen with first-line osimertinib in FLAURA, and osimertinib is approved for first-line treatment and readily reimbursed by insurance companies. However, osimertinib is also an excellent drug for patients who develop the EGFR T790M resistance mutation to first-generation or second-generation EGFR TKI therapy, which in fact was its first indication based on results from the phase III AURA study (median progression-free survival [PFS]: 10.1 vs 4.4 months with chemotherapy; HR: 0.30; 95% CI: 0.23-0.41; P <.001). Thus, some countries are still choosing to sequence osimertinib in the second line after treatment with a first-generation or second-generation EGFR TKI because they think its frontline use is too costly. However, it should be remembered that across phase III trials of first-line EGFR TKI therapy, including FLAURA with possible crossover, approximately one third of patients did not receive a second-line therapy. Another issue with this strategy is that the chance of a patient developing a T790M mutation is only approximately 40% to 50%, and we cannot anticipate which patients will or will not develop this resistance mutation, so with this latter approach, approximately one half of all patients with EGFR-mutated NSCLC will never receive osimertinib, the best drug available for their disease. Furthermore, identification of the T790M mutation can be missed as it requires rebiopsy at the time of tumor progression, whether by tissue or plasma, which is not always successful because of access issues, small size of the tumor, or not enough circulating tumor DNA in plasma or because of the molecular technique used (eg, for liquid biopsy, assay sensitivity is only 70%). We lead with the best drug for our patients with ALK or ROS1-altered NSCLC to ensure that all patients receive the best treatment and must also do so for our patients with EGFR-mutated disease.

An additional potential barrier to a patient receiving osimertinib is access to molecular testing to identify the presence of an EGFR mutation. The current standard of care to guide choice of optimal therapy in the treatment of advanced NSCLC is to test for actionable mutations upon diagnosis regardless of PD-L1 expression level, particularly in nonsmoking or light smoking patients. Nowadays, we are using broad-based next-generation sequencing (NGS) to test for the entire suite of alterations with approved targeted therapies—not only EGFR but also ALK, ROS1, BRAF, RET, MET, NTRK, and KRAS. NGS testing spares some tissue, money, and time compared with sequential molecular analysis, and many countries are moving in that direction. However, disparities in its use and access remain.

What’s Next? Future Directions for Managing EGFR-Mutated NSCLC
Despite advances in the treatment of EGFR-mutated NSCLC, there is still more to be done as every patient who receives a first-line EGFR TKI, including osimertinib, will experience disease progression. There are ongoing efforts to understand the mechanisms of escape from third-generation EGFR TKIs such that we can adapt second-line treatment according to mechanism of resistance at progression as identified by NGS testing in a tissue or liquid biopsy. For example, results may indicate a MET amplification, an EGFR exon 20 mutation (eg, C797S, L718Q, L792F, or G796S), or a rarer alteration in HER2, PI3KCA, KRAS, BRAF, ALK, or RET, for which approved and effective targeted therapies are available, or it could identify a mutation qualifying them for enrollment on a clinical trial. The patient may fare better with standard platinum-based chemotherapy if a genomic alteration is not found at progression or transformation to small-cell histology is identified (for which we lean toward giving platinum-etoposide chemotherapy). I would also like to note the recent encouraging results presented at the 2021 American Society of Clinical Oncology annual meeting for the anti-HER3 antibody–drug conjugate patritumab deruxtecan in the post-osimertinib setting: Patritumab deruxtecan achieved a confirmed objective response rate of 39% (95% CI: 24%-55%) in patients with EGFR-mutated advanced NSCLC previously treated with osimertinib and platinum-based chemotherapy, a benefit that was observed regardless of the level of HER3 expression or mechanism of resistance to osimertinib.

We also need better options for monitoring patients for progression. We currently monitor patients with a CT scan and wait for radiologic progression, but soon, we may have methods for molecular monitoring, namely, looking for clearance of circulating tumor DNA positive for the original EGFR mutation in a liquid biopsy after 4 or 6 weeks of EGFR TKI therapy and using this to better predict which patients will have a major response or early recurrence of disease. This approach will also be important to anticipate resistance before clinical or radiologic progression and to identify its mechanism to tailor therapy, as discussed above.

Combination therapy with an EGFR TKI is also being investigated for the treatment of EGFR-mutated NSCLC. We have seen promising PFS results with EGFR TKIs in combination with platinum-based chemotherapy (eg, the phase III FLAURA2 trial of osimertinib with or without carboplatin or cisplatin plus pemetrexed [NCT04035486]) or antiangiogenic therapies, like bevacizumab and ramucirumab, in the frontline setting, and clinical trials are ongoing. The presence of comutations (eg, MET, TP53, CDK4/5, PIK3CA) may also drive the use of combination therapy. For example, MET resistance mutations can be de novo mutations that, if you only inhibit mutant EGFR, may have an early evolution and lead to early resistance to the EGFR TKI. In this scenario, the use of selective MET inhibitors, like capmatinib, tepotinib, or savolitinib, in combination with first-line osimertinib may thwart the evolution of resistance to this EGFR TKI via MET. I can also see first-line treatment with the EGFR-MET–bispecific antibody amivantamab, which currently has an approval in the United States for EGFR exon20ins–positive NSCLC with progression on or after platinum-based chemotherapy and has shown promising results in the setting of post-osimertinib disease, being useful in this setting. In fact, the phase III MARIPOSA study comparing amivantamab plus the third-generation EGFR TKI lazertinib vs osimertinib for advanced EGFR-mutated NSCLC is underway (NCT04487080). That said, we have a lot to learn about the impact of de novo comutations on the development of early resistance to osimertinib in EGFR-mutated advanced NSCLC, but I can imagine a future where this population will be divided into patients with an EGFR mutation alone or those with some comutation with regard to treatment decisions. 

The management of patients with uncommon EGFR mutations (eg, those in exon 18 or exon 20 insertions), for which afatinib or osimertinib may be effective, also needs to be better determined. Efforts to develop new EGFR TKIs targeting these uncommon EGFR mutations are ongoing, with the most promising results currently being in the setting of exon 20 insertions. The EGFR TKIs mobocertinib, poziotinib, CLN-081 (TAS6417), and DZD9008 have demonstrated antitumor activity against these mutations but often with greater toxicities, particularly grade 3/4 diarrhea and skin rash. Furthermore, as mentioned above, amivantamab was recently approved in the United States for EGFR exon20ins–positive NSCLC with progression on or after platinum-based chemotherapy.

Finally, I also expect there to be an evolving role for immunotherapy in the treatment of EGFR-mutated NSCLC. Although initial results with immunotherapy in these patients, particularly as monotherapy, were quite disappointing, combination therapy has shown promise: In the phase III IMpower150 trial, atezolizumab in combination with carboplatin/paclitaxel chemotherapy and bevacizumab achieved an interesting improvement in PFS and overall survival in a subpopulation of patients with EGFR-mutated NSCLC pretreated with an EGFR TKI. The combination of an EGFR TKI with immunotherapy has also shown some limited efficacy but with increased toxicity; for example, the combination of osimertinib plus durvalumab led to notable pulmonary toxicity. Although phase III trials evaluating the optimal combination partner for upfront immunotherapy in this population of patients is ongoing, it is important to remember that -mutated NSCLC generally do not benefit from current immunotherapy-based regimensEGFRpatients with regardless of their level of PD-L1 expression. This reinforces the need to test for molecular alterations in nonsmoking and light smoking patients before starting any treatment, including immunotherapy even if PD-L1 expression is high.

Your Thoughts
In your current practice, what barriers have you encountered in the treatment of your patients with EGFR-mutated advanced NSCLC? I encourage you to answer the polling question and join the conversation by posting in the discussion section below.