Pfizer's Dacomitinib, Dubbed 'The Strongest Second-Generation EGFR-TKI,' Nears China Approval

Author: Cai Cai

On May 7, the NMPA website showed that the approval status of Pfizer’s second-generation EGFR-TKI dacomitinib (English name: Dacomitinib, brand name: Vizimpro) for marketing application has changed to “Under Review,” and the drug is highly likely to be approved for marketing this month.

(Data source: NMPA official website)

"The World's First Second-Generation EGFR-TKI" Afatinib--Poor OS, significant side effects

Tyrosine kinase inhibitors (TKIs) are targeted therapies that have emerged alongside advances in cancer molecular subtyping and molecular biology. By inhibiting key nodes within intracellular signaling pathways, they block pathway transmission and thereby suppress tumor growth. Among these, EGFR-TKIs have become the NCCN-recommended first-line treatment due to their remarkable clinical efficacy in EGFR-positive non-small cell lung cancer (NSCLC), a major cancer subtype accounting for approximately 30% of all lung cancer cases. After more than a decade of research and development, currently marketed EGFR-TKIs are primarily classified into three generations:

(Compiled from public sources)

Afatinib (English name: Afatinib, brand name: GIOTRIF), despite being hailed as the "world's first second-generation EGFR-TKI," has remained highly controversial. In head-to-head trials comparing it with the first-generation EGFR-TKI gefitinib for first-line treatment of patients with EGFR-positive non-small cell lung cancer (NSCLC), afatinib did not demonstrate significant clinical advantages. Results from the LUX-LUNG 7 clinical trial indicated that afatinib failed to meet expectations for a substantial breakthrough, particularly showing no significant improvement in overall survival (OS) (24.5 vs. 27.8 months). Meanwhile, afatinib was associated with greater adverse effects than first-generation agents, leading many patients to discontinue treatment due to intolerable side effects such as diarrhea and rash. These factors collectively contributed to its suboptimal market performance following approval.

"The Strongest Ever" Second-Generation EGFR-TKIOutperformed gefitinib and afatinib

It was precisely against the backdrop of afatinib’s suboptimal performance that dacomitinib emerged.

Dacomitinib is an experimental, oral, once-daily, irreversible second-generation EGFR-TKI. It was approved by the FDA on September 27, 2018, for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring 19del and 21-L858R mutations. The application was accepted by the CDE on May 21, 2018, granted priority review status in July 2018, and its approval status was updated to “under review” in May 2019.

OS: Dacomitinib decisively outperforms gefitinib

In the 2018 ARCHER 1050 trial, second-generation dacomitinib was compared head-to-head with first-generation gefitinib for the treatment of patients with EGFR-positive non-small cell lung cancer (NSCLC). The latest clinical data presented at the 2018 ASCO Annual Meeting showed:

(1) Dacomitinib and gefitinib had similar objective response rates of 75% and 72%, respectively; however, dacomitinib demonstrated a progression-free survival (PFS) of 14.7 months and a duration of response of 14.8 months, representing a six-month improvement over gefitinib. In simpler terms, the second-generation agent dacomitinib is less prone to drug resistance.

(Data source: ASCO 2018)

(2) The overall survival (OS) for patients in the dacomitinib group reached 34.1 months, nearly 3 years, representing a 7.3-month improvement over the 26.8 months observed with gefitinib. The 30-month OS rate was 56.2% compared to 46.3% for gefitinib, demonstrating clear superiority over first-generation gefitinib in terms of OS.

(Data source: ASCO 2018)

The survival benefit of dacomitinib was consistent across all subgroup analyses, including different ethnicities and EGFR mutation types. This study suggests that dacomitinib should be considered as one of the standard treatment options for patients with advanced EGFR-mutated non-small cell lung cancer.

Fewer side effects than afatinib; no contraindications

Notably, dacomitinib has no contraindications and exhibits fewer side effects than afatinib.

(Data source: FDA official website)

Huadong Medicine's Second-Generation EGFR TKI: MafatinibAlso actively expanding its presence in China

Furthermore, Huadong Medicine’s mafatinib is a potent irreversible dual inhibitor of EGFR/HER2 and belongs to the second-generation EGFR-TKIs. It has currently entered Phase II clinical trials for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-sensitive mutations, which is promising.

(Data sourced from the "Drug Clinical Trial Registration and Information Publicity Platform")

Lung cancer is one of the leading causes of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all lung cancer cases. Statistics show that 75% of NSCLC patients have metastatic or advanced-stage disease at the time of diagnosis, and their five-year survival rate is only 5%. EGFR is a protein that facilitates cell growth and division. Mutations in the EGFR gene lead to overactivation of the protein, thereby promoting carcinogenesis. EGFR gene mutations occur in 10–35% of NSCLC patients, with the most common activating mutations being exon 19 deletions and the exon 21 L858R substitution, which together account for 80% of known activating EGFR mutations. The treatment of such tumors remains a significant challenge.