The landscape of non-small cell lung cancer (NSCLC) treatment has transformed dramatically in recent years, with targeted therapies and immunotherapies revolutionizing patient outcomes. While the US has approved many innovative treatments, several promising therapies have emerged in international markets, particularly in China, that are not yet available to American patients. This blog explores these novel treatments, their efficacy in specific NSCLC populations, and their potential pathway to US approval.
The Expanding World of EGFR Tyrosine Kinase Inhibitors
Aumolertinib (Almonertinib): A Third-Generation EGFR-TKI with Impressive Results
Aumolertinib (formerly known as almonertinib and marketed as Ameile® in China) represents an important advancement in the treatment of EGFR mutation-positive NSCLC. This third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) is selective for mutant EGFR over wild-type EGFR, potentially reducing side effects associated with wild-type EGFR inhibition.
Indications and Efficacy: Aumolertinib has been approved in China for both first-line treatment of EGFR mutation-positive NSCLC and second-line treatment for patients with T790M mutation-positive NSCLC who have progressed after prior EGFR-TKI therapy.
In the phase 3 AENEAS trial with Chinese patients, first-line aumolertinib significantly prolonged progression-free survival (PFS) and duration of response compared to gefitinib in patients with advanced EGFR mutation-positive NSCLC. For second-line treatment, the phase 1/2 APOLLO trial demonstrated good clinical activity in patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who had progressed on previous EGFR-TKI therapy.
A comparative study published in 2023 suggested that aumolertinib may have superior efficacy compared to osimertinib (which is approved in the US) in T790M-positive patients, with higher objective response rates (70.0% vs. 47.5%) and disease control rates (90.0% vs. 77.5%).
Safety Profile: Aumolertinib demonstrates a generally manageable tolerability profile. Interestingly, adverse events associated with wild-type EGFR inhibition (such as rash and diarrhea) were less frequent with aumolertinib than with gefitinib in the AENEAS trial.
US Availability Outlook: While no specific timeline for US approval has been announced, the impressive efficacy data and favorable safety profile make aumolertinib a strong candidate for future FDA review.
Furmonertinib: Targeting EGFR Exon 20 Insertions and Beyond
Furmonertinib is an oral, highly brain-penetrant, broadly active mutant-selective EGFR inhibitor designed to target EGFR exon 20 insertions and other EGFR mutations.
Indications and Efficacy: Furmonertinib is approved in China for first-line treatment of advanced NSCLC with EGFR exon 19 deletion or L858R mutations based on the progression-free survival benefit observed in the Phase 3 FURLONG study versus gefitinib.
What makes furmonertinib particularly promising is its activity against EGFR exon 20 insertion mutations, which occur in approximately 2% of NSCLC cases and have historically been challenging to treat. In the FAVOUR study, treatment-naïve patients with NSCLC harboring EGFR exon 20 insertion mutations showed a remarkable confirmed overall response rate of 78.6% by blinded independent central review, with a preliminary median duration of response of 15.2 months.
US Availability Outlook: Furmonertinib recently received FDA Breakthrough Therapy Designation for the first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertion mutations. This designation could accelerate its review process, suggesting it might be among the first of these international drugs to reach the US market. The FURVENT Phase 3 trial comparing furmonertinib versus chemotherapy in this setting will likely be pivotal for FDA consideration.
Alflutinib: Another Contender in the EGFR T790M Space
Alflutinib (AST2818) is another third-generation EGFR-TKI developed in China for EGFR mutation-positive NSCLC.
Indications and Efficacy: Alflutinib has shown significant clinical activity in patients with advanced NSCLC with confirmed EGFR T790M mutation whose disease progressed after first- or second-generation EGFR-TKI therapy. In a phase IIb multicenter study, alflutinib demonstrated an impressive objective response rate of 73.6% and a median PFS of 7.6 months.
Importantly, alflutinib has also shown efficacy in patients with central nervous system (CNS) metastases, with a response rate of 70.6% in this difficult-to-treat population. This is particularly significant as CNS metastases are common in EGFR-mutated NSCLC and represent a major treatment challenge.
Safety Profile: Alflutinib appears to be well-tolerated, with most adverse events being grade 1 or 2. In clinical trials, the most common adverse events included increased aspartate aminotransferase, upper respiratory tract infection, and cough.
US Availability Outlook: While specific plans for US approval have not been publicized, the promising efficacy and safety data could position alflutinib as a future competitor in the US market for EGFR T790M-positive NSCLC.
Icotinib: An Established EGFR-TKI in China
Icotinib is an EGFR-TKI that has been used in China for treating patients with NSCLC.
Efficacy and Safety: A systematic analysis of icotinib treatment across multiple studies involving 5,985 Chinese patients with NSCLC found a pooled response rate of 30.1%. The main side effects were mild skin itching, rashes, and diarrhea, with no grade III or IV renal or liver toxicity observed and no treatment-related deaths.
US Availability Outlook: Given its established presence in China but relatively modest response rates compared to newer EGFR-TKIs, icotinib may not be a priority for US market entry.
Lazertinib: Addressing the Challenge of CNS Metastases
Lazertinib is a third-generation EGFR-TKI that has been studied particularly for its CNS activity.
Indications and Efficacy: Lazertinib has demonstrated substantial CNS activity in patients with EGFR-variant NSCLC whose CNS metastases progressed after treatment with first-generation or second-generation EGFR-TKIs. A multicenter phase 2 trial in South Korea showed a median intracranial progression-free survival of 15.8 months, regardless of T790M status. The cerebrospinal fluid penetration rate of lazertinib was 46.2%, providing mechanistic support for its intracranial efficacy.
Safety Profile: Most adverse events with lazertinib were grade 1 or 2, making it a well-tolerated option for patients with CNS involvement.
US Availability Outlook: With its specialized efficacy in CNS metastases, lazertinib could fill an important niche in the US market, but no specific approval timeline has been announced.
ALK Inhibitors: New Options for ALK-Positive NSCLC
Ensartinib: Nearing US Approval
Ensartinib is an ALK inhibitor that has shown promising results in ALK-positive NSCLC.
Indications and Efficacy: Ensartinib is indicated for adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic NSCLC who have not previously received an ALK inhibitor.
Safety Profile: Common ensartinib-related adverse events include rash (67.8%), increased liver enzymes, pruritus (26.6%), nausea (22.4%), constipation (20.3%), and edema (21.0%). While most adverse events are grade 2 or lower, grade 3 rash occurred in 11.2% of patients but was manageable with dose modifications.
US Availability Outlook: Ensartinib has made significant progress toward US approval. The FDA accepted the new drug application for ensartinib on March 13, 2024, and subsequently approved it on December 18, 2024. This makes ensartinib the most recent addition to the US market among the drugs discussed in this blog.
MET Inhibitors: Targeting Another NSCLC Driver Mutation
Savolitinib: First Selective MET Inhibitor Approved in China
Savolitinib (ORPATHYS®) is an oral, potent, and highly selective MET tyrosine kinase inhibitor.
Indications and Efficacy: Savolitinib is approved in China for the treatment of adult patients with locally advanced or metastatic NSCLC with MET exon 14 skipping alteration, representing the first selective MET inhibitor approved in China. It has been included in the National Reimbursement Drug List of China since March 2023.
In a Phase IIIb study in China, savolitinib demonstrated significant survival benefits in MET exon 14 skipping alteration NSCLC. In treatment-naïve patients, the median overall survival was 28.3 months, with a 36-month OS rate of 44.7%. In previously treated patients, the median OS was 25.3 months, with a 24-month OS rate of 51.7%.
US Availability Outlook: In 2023, savolitinib in combination with TAGRISSO® received Fast Track Designation from the US FDA, suggesting a potential pathway to US approval, particularly for combination therapy in EGFR-mutated NSCLC with MET-driven resistance.
Immune Checkpoint Inhibitors: Global Innovation
Sintilimab: Promising Results in Squamous NSCLC
Sintilimab is an anti-PD-1 antibody that has shown effectiveness in combination with chemotherapy for squamous NSCLC.
Indications and Efficacy: A phase 2 clinical trial investigated sintilimab in combination with just two cycles of nab-paclitaxel/carboplatin, followed by sintilimab maintenance therapy in patients with advanced squamous NSCLC. The results were impressive, with a median PFS of 11.4 months, an objective response rate of 70.5%, and a disease control rate of 93.2%. The median overall survival reached 27.2 months.
Safety Profile: Treatment-related adverse events of grade 3 or higher occurred in only 10.9% of patients, suggesting a favorable safety profile.
US Availability Outlook: While no specific US approval plans have been announced, the strong efficacy data with limited chemotherapy exposure could make this an attractive approach for US patients.
Other Notable Immune Checkpoint Inhibitors
Several other immune checkpoint inhibitors have shown promise in international markets:
Toripalimab: In combination with chemotherapy for first-line treatment of advanced NSCLC, toripalimab significantly improved both PFS and OS compared to chemotherapy alone.
Camrelizumab: Real-world experience with camrelizumab in China has shown a median PFS of 12.6 months and a median OS of 22.3 months in NSCLC patients.
Serplulimab: When added to chemotherapy for advanced squamous NSCLC, serplulimab significantly improved survival with manageable safety.
Adebrelimab: Though primarily studied in small cell lung cancer, adebrelimab plus chemotherapy significantly improved overall survival compared to chemotherapy alone (15.3 vs. 12.8 months).
Conclusion: What This Means for US Patients
The global landscape of NSCLC treatment continues to evolve rapidly, with significant innovation occurring outside the United States, particularly in China. These emerging therapies offer new hope for patients with specific molecular subtypes of NSCLC, including those with difficult-to-treat mutations like EGFR exon 20 insertions and those with CNS metastases.
For US patients and oncologists, several of these treatments appear to be on track for potential FDA approval in the coming years. Furmonertinib’s Breakthrough Therapy Designation and savolitinib’s Fast Track Designation signal accelerated review pathways, while ensartinib has already gained FDA approval as of December 2024.
The global nature of clinical research in NSCLC highlights the importance of international collaboration and regulatory harmonization to ensure that promising therapies can reach patients worldwide in a timely manner. As these novel agents progress through various stages of development and regulatory review, they offer the promise of expanded treatment options and improved outcomes for patients with NSCLC in the United States and beyond.
As with all cancer therapies, the ultimate value of these treatments will depend not only on their efficacy but also on their safety profiles, cost-effectiveness, and ability to address unmet medical needs in specific patient populations. The continued evolution of precision medicine in NSCLC represents a significant step forward in our ability to provide personalized, effective care to patients facing this challenging diagnosis.
Source: Journal of Clinical Oncology; FDA; Nature; Cancel Cell; wiley
