Befotertinib: one more drug targeting EGFR—the more may be the merrier

The treatment paradigms of locally advanced and metastatic non-small cell lung cancer (NSCLC) have evolved significantly with the discovery of actionable mutations and the development of targeted therapies (1). Among these mutations, those affecting the epidermal growth factor receptor (EGFR) can be considered representatives of these advances. The multitude of EGFR tyrosine kinase inhibitors (TKIs) allied with the relatively high-frequency of EGFR mutations in this patient population underscore the relevance of this target in clinical practice. The incidence of EGFR mutations is higher in Asian populations, where it can occur in over 50% of patients (2). Meanwhile, in western populations, it occurs in around 16% of patients (3). This difference explains the number and pertinence of clinical trials with new and different EGFR TKIs originated from Asia.

The successful history of targeting EGFR in NSCLC is evidenced by the number of EGFR TKIs that have been developed, approved, and employed in clinical practice (4). First-generation agents, such as erlotinib, gefitinib, and icotinib, and second-generation drugs, exemplified by afatinib, have been approved and utilized with favorable outcomes. However, there are resistance mechanisms that develop after exposure to these medications. Development of T790M mutation is one of the main mechanisms underlying this process (5). This mutation leads to modifications in the binding pocket of 1^st generation drugs, preventing them from binding to EGFR. Different EGFR mutations may also lead to resistance, with some being discussed later in the text. Other mechanisms of resistance, however, involve activation of downstream signaling pathways. The main example being MET amplification, affecting pathways such as PI3K/AKT, RAS/MAPK, and STAT3, regardless of EGFR mutation status or inhibition (6). In this space, third-generation EGFR TKIs flourished, as they were shown to be effective even in NSCLC harboring the T790M mutation. Osimertinib is one of the most known examples of this group (7). It was initially approved in the 2^nd line after patients had disease progression and development of T790M mutation, but its superior efficacy, compared to 1^st generation TKIs, was later confirmed in the 1^st line, leading to its approval in the frontline setting by the United States Food and Drug Administration in 2018 (8). Osimertinib was also approved by the Chinese National Medical Products Administration (NMPA), alongside aumolertinib, and furmonertinib, with both following similar approval steps until final adoption in the 1^st line (9). Another new third-generation drug is befotertinib. Befotertinib has shown efficacy and was approved by the Chinese NMPA in the 2^nd line for patients with locally advanced or metastatic NSCLC who received previous EGFR TKI therapy and had disease progression and confirmed T790M mutation (10). Subsequently, and similarly to other third-generation TKIs, befotertinib was studied and compared to the first-generation TKI in the 1^st line setting.

Lu et al. conducted a prospective phase 3 study comparing the use of befotertinib, versus icotinib, as 1^st line treatment in patients with unresectable locally advanced or metastatic NSCLC with EGFR mutations, either exon 19 deletions or exon 21 L858R point mutations (11). This study was a multicenter, open-label, randomized trial that enrolled patients from 39 hospitals in China between December 24, 2019 and December 18, 2020. A total of 362 patients were enrolled, 182 in the befotertinib group and 180 in the icotinib group. Patients received treatment until disease progression, and possibly beyond progression, when deemed clinically beneficial by investigators. Upon progression, patients in the icotinib group were allowed to cross-over to befotertinib if an EGFR T790M mutation was diagnosed at the time of progression (11).

Results of the study showed that the primary endpoint of independent review committee (IRC)-assessed progression-free survival (PFS) was met, with a median PFS in the befotertinib group of 22.1 months [95% confidence interval (CI): 17.9 months–not estimable], and a median PFS in the icotinib group of 13.8 months (95% CI: 12.4–15.2) (hazard ratio =0.49, 95% CI: 0.36–0.68, P<0.0001). The secondary endpoint of overall survival (OS) was not mature at the time of the publication.

Subgroup analysis of PFS results showed that befotertinib was superior to icotinib in patients harboring EGFR exon 19 deletion. For those with exon 21 L858R point mutations, PFS was numerically superior with the study drug, but not statistically different (hazard ratio =0.63, 95% CI: 0.37–1.08, P=0.088) (10). This difference has also been seen with other drugs in the same class. Although osimertinib, aumolertinib, and furmonertinib have lower hazard ratios for PFS in patients with L858R mutations, the difference was still statistically superior to their respective control groups (8,12,13). The non-statistically significant results with befotertinib may be explained due to the lower number of patients with this mutation enrolled in the trial (65 patients), and possibly by the time of response assessment, as further differences may be unveiled as data matures. However, possible pharmacological differences may also be responsible for this outcome, considering subtle distinctions at the befotertinib binding site in the receptor.

As far as safety data, grade 3 or higher treatment-related adverse events (AEs) were reported in 30% of patients who received befotertinib, and 8% of patients who received icotinib. The most common AEs were thrombocytopenia (9%) and pulmonary embolism (6%) with befotertinib, and alanine aminotransferase (ALT) elevation (3%) and aspartate aminotransferase (AST) elevation (2%) with icotinib (10). Importantly, quality of life assessed by the Functional Assessment of Cancer Therapy-Lung Cancer (FACT-L) did not differ statistically between both groups.

The AEs profile of befotertinib and its dosing regimen present some unique characteristics. It is administered at a starting dose of 75 mg daily for 21 days, with the possibility of dose increase to 100 mg daily if grade 2 or higher thrombocytopenia or headache did not occur over the initial 3 weeks. Uniquely, toxicities include thrombocytopenia and pulmonary embolism, which are not commonly observed with the other third-generation TKIs.

Befotertinib’s results are comparable to other drugs in the same class. Osimertinib, aumolertinib, and furmonertinib have demonstrated comparable efficacy and PFS results in their respective trials (8,12,13). Results from the four clinical trials are listed in Table 1. As demonstrated in the table, each drug has particularities related to their outcomes. Befotertinib has the highest median PFS numerically in all patients and those with central nervous system (CNS) metastases, while osimertinib has the highest objective response rate (ORR). CNS ORR, however, is higher with furmonertinib. These cross-trial comparisons should be made with caution, especially considering differences in baseline population characteristics and geographic locations of each trial, but may underscore some of the unique features of each drug.

The overall incidence of AEs was also similar amongst the four drugs. However, their toxicity profiles showed significant differences. Patients who received osimertinib often presented with dermatologic and gastrointestinal AEs, such as rash, diarrhea, and paronychia (7). Aumolertinib was associated with creatine phosphokinase, ALT, and AST increase, alongside dermatologic and gastrointestinal AEs as well (12). In those treated with furmonertinib, ALT and AST elevation, diarrhea, and rash were also the most common toxicities (13). However, for befotertinib, as mentioned above, thrombocytopenia, headache, and pulmonary embolism stood out as the most common AEs (11).

The variations in AEs and their management are also pertinent to treatment decisions. Those treated with befotertinib, for example, may require anticoagulation during their treatment course if they develop pulmonary embolism. However, despite these differences, quality of life did not differ significantly between the intervention and control arms, as described above.

It is worth mentioning that befotertinib was assessed in patients with an ECOG performance status of 0–1, similarly to studies with other third generation TKIs. In real-world clinical practice, some patients with poorer performance status are being treated with TKIs, and therefore inclusion of these patients in future trials and assessing their long-term outcome including efficacy and toxicity is essential and necessary.

Importantly, a major endpoint that is essential to real-world clinical practice is OS. Although not mature at the time of the article publication, the available data was numerically higher for befotertinib. The estimated 30-month OS for befotertinib was 67.3%, compared to 60.3% for icotinib (11). From the four drugs in this class, median OS is mature for osimertinib only. Once mature, OS data may assist further in the decision of drug selection.

The now expanding availability of EGFR TKI raises questions regarding the role and applicability of each of these drugs. Despite an apparent overlap in mechanism and no major discrepancies in efficacy benefit, the discovery of new targeted therapies, even when directed against a same target, can be advantageous. From a social and health equity standpoint, the presence of more drugs may pave the way for competition between companies and their molecules, potentially leading to improved cost-effectiveness. The ultimate results may be a decrease in cost of medications to patients and health systems and increased availability of these newer therapies (17). Considering the differences in EGFR mutation prevalence related to geographic areas, drugs may be adopted preferentially in specific countries or territories. Having said that, the availability and approval of these drugs still vary significantly among different countries, with some of them not being widely offered, unfortunately. This may also be explained by the site where the clinical trials were conducted. The befotertinib trial, similar to the aumolertinib and furmonertinib trials, was conducted in China. Despite the sample size, this geographic limitation may pose challenges when extrapolating the outcomes to other populations, ethnicities, or locations.

From a medical and biological perspective, the subtle differences between each of these drugs may justify their existence. Variations in the AE profile and, potentially, in outcomes in specific groups, may be the determinant factors of when to prescribe one drug versus the other (18). This also applies to resistance mechanisms. As previously reported, T790M mutation is a molecular mechanism of resistance to first-generation EGFR TKI (19). Newer generation drugs, such as osimertinib, can target these resistance mutations, leading to improved outcomes (20). Other drugs in this class, including befotertinib, have similar properties. Nonetheless, resistant mutations still arise against third generation TKI. A noteworthy example is the acquired C797S mutation (21). Some case reports demonstrated ways of addressing this mechanism of resistance using gefitinib, a first-generation EGFR TKI (22,23). It is yet to be determined, but considering the unique molecular structures of each drug, one could speculate that combining earlier and later generation drugs could represent potential ways to overcome resistant mutations.

Combinations of a third-generation EGFR TKI and other drugs have recently demonstrated relevant outcomes in larger clinical trials as well. Some examples include the association of osimertinib and platinum-doublet chemotherapy, and the utilization of amivantamab, an EGFR-MET bispecific antibody, combined with chemotherapy with or without lazertinib, a third-generation EGFR TKI (24,25). Both studies strengthen the concept that future combinations may arise, becoming potentially approved options in the first or posterior lines of therapy. A significant caveat of these possible combinations is their toxicity, as they are associated with more significant AEs. Tolerability may vary based on patient populations and their comorbidities, which should be very carefully considered in clinical practice and addressed in future trials.

Another intriguing benefit that may come with more drug options available is the potential of cycling between these agents. Traditionally, rechallenging a patient with same EGFR TKI, after disease progression on another interval therapy, or cycling through different targeted therapies are not considered standard of care management. Understandably, once progression occurs, it is believed that resistance mechanisms will preclude a disease response to that previously used drug or another drug from the same class. However, this concept has been challenged, with some studies demonstrating a potential role for further utilizing and exploring these options in patients with advanced and metastatic NSCLC, as well as in those who received osimertinib in the adjuvant settings (26-28). Nonetheless, well-designed clinical trials are required to address this question.

Ultimately, these possibilities and reflections culminate with the conclusion that having more drugs available, even for a same molecular target, is beneficial to patients and health systems. Befotertinib is a remarkable example of this. A new drug that achieved its primary outcomes in a clinical trial may join the group of already approved and more widely used medications. The prospect benefits of it also highlight a vast array of questions and uncertainties.

Further research is necessary to determine whether combining, sequencing, or cycling through EGFR TKIs are appropriate strategies for the population harboring these mutations. Basic, translational, and clinical research is essential for this determination. From studies focused on the molecular mechanisms of drug resistance, to clinical and epidemiological investigations of the differences between EGFR mutations in specific populations, future data will help guide the most effective and appropriate way to utilize the constantly growing arsenal of drugs available for patients with NSCLC with EGFR mutations. As these advancements continue to happen, the importance of next-generation sequencing in cancer diagnosis cannot be underscored. Besides guiding management and understanding the disease biology, it continues to become a relevant tool in the event of disease progression, also guiding therapy in this setting.

Clinical trials comparing different targeted therapies, such as befotertinib and icotinib, are important to update and broaden the standard care options available for patients. An in-depth analysis of the specificities of results, safety profile, and particularities of each of these newer drugs provides the basis for better and more personalized patient care. The wider availability of options may also pave the way for increased access to newer drugs, with potentially improved clinical outcomes. In the rapidly evolving field of oncology, the more options available for patients may be the merrier.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-50/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-50/coif). Y.L. has received research funding support from Merck, Tolero Pharmaceuticals, AstraZeneca, Blueprint Medicines, Sun Pharma, Mirati Therapeutics, Genmab, EMD Serono, Jacobio Pharma, TOPALLIAN, and Daiichi Sankyo; and participated in the advisory board for AstraZeneca Pharmaceuticals, Janssen Pharmaceutical, Lilly Oncology, Turning point therapeutics, Oncohost, and Mirati Therapeutics (Honorarium to Mayo Clinic). R.M. participated in the advisory board for AstraZeneca Pharmaceuticals, Novocure, Oncohost and Janssen Pharmaceutical. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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