Befotertinib in first-line treatment for Chinese non-small cell lung cancer patients harboring common EGFR-mutations reveals similar efficacy to other third-generation EGFR-TKIs but somewhat different safety profile

The introduction of the third-generation (3G) epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), osimertinib, aumolertinib, furmonertinib and lazertinib, have in phase III studies for advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients demonstrated improved efficacy compared to first-generation (1G) EGFR-TKIs. This is shown in comparisons to erlotinib or gefitinib in terms of progression-free survival (PFS), intracranial activity, and overall survival (OS) (1-5). Lu et al. recently reported on a phase III study on a new, oral 3G EGFR-TKI, befotertinib, which was compared to the 1G EGFR-TKI, icotinib, after median follow-up of 20.7 months (6). The study was conducted solely in Chinese patients. Icotinib had previously not been compared with a 3G EGFR-TKI but was approved by the China Food and Drug Administration (CFDA) in 2011 as a treatment for NSCLC with EGFR-mutations based on the results of the ICOGEN phase III trial, showing its non-inferiority versus the other 1G EGFR-TKI, gefitinib. The study showed a median PFS for patients treated with icotinib and gefitinib of 4.6 and 3.4 months, respectively, and fewer treatment-associated adverse events (AEs) with icotinib (7). In November 2014, icotinib became the second EGFR-TKI approved by the CFDA for first-line therapy of advanced EGFR-mutated NSCLC, after gefitinib. The present standard of care in China is osimertinib, which was approved based on the results of the FLAURA China study displaying the superiority of osimertinib (17.8 months) versus an EGFR-TKI comparator such as erlotinib or gefitinib (9.8 months) in terms of PFS (1).

Befotertinib represents another new 3G EGFR-TKI and is already approved in China as a second-line treatment for EGFR-mutated NSCLC-patients, who have disease progression associated with acquired EGFR T790M mutation (8). The current study by Lu et al. (6) aimed to compare efficacy of befotertinib with a 1G EGFR-TKI, icotinib, broadly used in Asia. The study was conducted in 39 hospitals in China and recruited 362 patients with histologically or cytologically verified NSCLC of adenocarcinoma type harboring the most common sensitizing EGFR-mutations, i.e., exon 19 deletion (ex19del) or the missense mutation L858R in exon 21. Yet, the molecular characterization of the analyzed samples from the enrolled patients is somehow unclear. The authors state that these EGFR-mutations were confirmed by “tissue biopsy” at a central laboratory, but it is not specified whether this sample sent to central molecular analysis was a new ad hoc tumor biopsy or the initial diagnostic biopsy, and in the latter case whether only histological (“tissue”) biopsies or also cytological specimens were used. Moreover, neither the method for assessing the EGFR-mutations [polymerase chain reaction (PCR)? next-generation sequencing (NGS)? other?] nor information about possible clinically relevant genomic co-alterations were provided.

In the study, 182 patients received befotertinib and 180 patients icotinib. Most patients in both arms were females, never smokers, in TNM stage IV, performance status (PS) 1, and harboring EGFR ex19del 64% and 65%, while L858R occurred in 36% and 35% in the two arms, respectively. The primary endpoint was PFS assessed by an independent review committee (IRC). PFS was significantly longer in the befotertinib group, 22.1 months [95% confidence interval (CI): 17.9–not estimable] compared to 13.8 months (95% CI: 12.4–15.2) in the icotinib group [hazard ratio (HR) =0.49, P<0.0001]. Importantly, treatment beyond progression was permitted for patients who obtained a clinical benefit both in the befotertinib and icotinib groups. Furthermore, patients randomized to the treatment with icotinib were allowed cross-over to befotertinib if they showed progression by RECIST criteria and acquired EGFR T790M mutation confirmed by tumor tissue re-biopsy, though this was not mandatory. In the icotinib group, only 14% of patients were crossed-over to befotertinib after progression and acquired EGFR T790M mutation. After progression, 19% and 51% of patients in the befotertinib and icotinib arm, respectively, received another 3G EGFR-TKI.

Since treatment beyond progression and cross-over were allowed, differences in OS between the two groups could not be assessed at the time of cut-off. The preliminary OS rates at 12 and 24 months did not display any significant difference between the two drugs (87.3% and 67.3% for befotertinib versus 88.3% and 70.7% for icotinib), but more mature data are awaited. The authors also reported a significant difference in median IRC-assessed PFS between the two treatments in patients with baseline central nervous system metastases [befotertinib 19.4 months (95% CI: 12.5–not estimable) versus icotinib 13.7 months (95% CI: 10.4–15.2); HR =0.48 (95% CI: 0.28–0.84], P=0.0086]. This finding is clinically important and confirms intracranial activity of befotertinib, which was a secondary endpoint of the study. However, only 32% of patients in both study arms had brain metastases, which may have affected the results. Thus, the percentage of patients with brain metastases in the study may somehow be lower than expected in an EGFR-mutated population.

The AE profile was comparable to the previously reported in EGFR-TKIs. The most common treatment-related AE of any grade for befotertinib was thrombocytopenia (58%), which was much more frequent than in the icotinib group (4%). Thrombocytopenia was also the most common AE of grade ≥3 in befotertinib-treated patients, while it was never observed as grade ≥3 in the icotinib group. Other AEs more common for the befotertinib than icotinib group were headache, musculoskeletal pain, anemia and hypercreatinemia. Furthermore, befotertinib was associated with increased risk of venous thromboembolism and pulmonary embolism (21% versus 1% for icotinib), an AE not frequently observed with other 3G EGFR-TKIs, and the mechanism of which remains to be elucidated. Subgroup analysis of PFS revealed significantly longer PFS for befotertinib than icotinib among patients with EGFR ex19del and a non-significant trend favorizing PFS in befotertinib-treated patients under 65 years of age. No significant difference in patients’ quality of life was observed between the two groups.

In conclusion, the study documented better systemic and intracranial efficacy in PFS of befotertinib versus icotinib as first-line therapy in Chinese patients with advanced NSCLC harboring the EGFR ex19dels and L858R mutations. However, as a note of caution one should consider that the disease of these patients differs in several aspects, not least drug efficacy and safety, as compared to populations of other ethnicity (9), as also highlighted by the authors (6). This limits extrapolations of the current data for befotertinib to the global genomic subtype of NSCLC patients with common EGFR-mutations. Additional limitation of the current trial is the fact that it is not a double-blinded study, which may result in biased approach to data interpretation. A minor point is that it lacks mature OS data, which are pending. Another issue is that also the comparator used in the study, icotinib, is not among the standard 1G EGFR-TKI utilized world-wide in populations having other ethnicities. In any case, befotertinib joins the group of other already approved effective 3G EGFR-TKIs (osimertinib, aumolertinib, and furmonertinib) as an additional first-line treatment option for Chinese patients with advanced EGFR-mutated NSCLC. Befotertinib efficacy against NSCLC with common EGFR-variants is comparable to that of the other 3G EGFR-TKIS, though with different safety profile due to increased risk of venous and pulmonary thromboembolism that may limit its clinical application and requires a thorough evaluation of this risk in patients receiving this drug. The approval for befotertinib in China as first line is—as far as we know—pending (10). The study by Lu et al. (6) did not extensively characterize the tumors molecularly in order to further expand on which patients would obtain the best clinical benefit from this drug. In particular, the mechanisms of intrinsic and acquired resistance to befotertinib, such as de novo and acquired genetic and phenotypic co-alterations remain to be elucidated.

Acknowledgments

Funding: 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-24-19/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-19/coif). J.B.S. has received honoraria for lectures, speaker fee, and advisory boards from Genmab, AstraZeneca, Merck, Novartis, Pfizer, Janssen, Bristol-Myers Squibb and Roche. E.S.R. has received honoraria for lectures and advisory boards from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Roche, and Takeda as well as research grants from Sanofi and Takeda. E.M.U. has received advisor and speaker honoraria from Amgen, AstraZeneca, Pfizer, Roche, Janssen, Novartis and Takeda as well as research funding from Pfizer, AstraZeneca, and Merck. The authors have no other conflicts of interest to declare.

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