Editor’s Note: With the discovery of lung cancer driver genes and the rapid development of drug research, targeted therapy for advanced non-small cell lung cancer (NSCLC) has made significant progress, and more rare targets in NSCLC are being discovered. At the recently held "2024 Academic Conference on Precision Diagnosis and Treatment of Lung Cancer," Dr. Yan Wang from the Cancer Hospital Chinese Academy of Medical Sciences presented on the "Advances in Research on Rare Mutations in NSCLC in 2024." In an interview with Oncology Frontier, Professor Wang further discussed hot topics regarding rare targets in NSCLC.Oncology Frontier: With the progress in the precise diagnosis of lung cancer, many rare/rare gene mutations have been discovered. First, could you briefly introduce the current hottest rare targets?
Dr. Yan Wang: Rare or infrequent target mutations typically refer to driver gene mutations with an incidence of less than 5%. In recent years, with the development of molecular testing techniques and targeted therapy research, more rare targets have been discovered in NSCLC patients, in addition to common targets such as EGFR-sensitive mutations. These rare targets have become a hot topic for new drug development. One category of rare targets is gene fusions, such as ALK fusion, ROS1 fusion, NTRK fusion, and MET fusion. Another category includes gene mutations, such as BRAFV600E, MET exon 14 skipping mutations, HER2 insertion mutations, KRAS G12C mutations, and non-classical mutations in the EGFR pathway (ex20ins, S768I, L861Q, G719X, etc.).
Currently, some drug developments targeting rare targets have made progress. For example, drugs targeting EGFR ex20ins, HER2 mutations, and KRAS G12C mutations have already been approved, but most are for second-line or later indications, and studies for first-line applications are ongoing.
Although the incidence of these rare mutations is relatively low, due to the large number of lung cancer patients, those with rare targets still warrant attention. Clinicians should focus on molecular testing when diagnosing NSCLC patients so that those with positive driver genes can benefit from targeted therapies and have better survival outcomes.
Oncology Frontier: As 2024 comes to an end, what new progress has been made this year in the field of NSCLC patients with rare gene mutations?
Dr. Yan Wang: This year, there have been several new developments in various rare target fields. Let me share some of the aspects that I find particularly interesting. The EGFR exon 20 insertion (EGFR ex20ins) mutation is the third most common EGFR mutation, following EGFR-sensitive mutations (Del19/L858R). The Phase III PAPILLON clinical trial, comparing evanotinib combined with chemotherapy to chemotherapy alone, showed positive results. Internationally, evanotinib combined with chemotherapy has been approved as the standard treatment for previously untreated advanced EGFR ex20ins patients. In terms of small molecule targeted drugs, suvorexant has already been approved for second-line indications in China. The WU-KONG1/15 pooled analysis showed that suvorexant as a single-agent first-line treatment for advanced NSCLC patients with EGFR ex20ins mutation achieved a confirmed objective response rate (cORR) of 78.6%. A Phase III clinical trial comparing suvorexant combined with chemotherapy to chemotherapy alone is ongoing, and we are looking forward to new clinical study results that may rewrite the guidelines.
The second very popular target is KRAS G12C. We know that KRAS G12C is a difficult target to drug. The first breakthrough was the FDA approval of the selective inhibitor Sotorasib for KRAS G12C in 2021, followed by the release of Adagrasib. These two drugs have been recommended by international guidelines as standard second-line treatment. However, the efficacy of KRAS G12C inhibitors as monotherapy still falls short of clinical needs. Attempts are being made to combine TKI with chemotherapy, immunotherapy, or SHP2 inhibitors targeting upstream pathways for first-line treatment. Early clinical research results show that KRAS G12C small molecule inhibitors as part of combination regimens in first-line treatment are also very promising.
The third popular target is HER2. The ADC trastuzumab deruxtecan (DS8201) was approved internationally a few years ago for second-line treatment and was recently approved in China for patients with HER2-activating mutations who have received at least one prior systemic treatment and have inoperable or metastatic adult NSCLC. There have been important research achievements domestically as well. In terms of small molecule TKIs, we conducted a study combining pyrotinib and apatinib as first-line treatment for HER2 gene mutation/amplification in advanced NSCLC patients. The study results showed that this regimen achieved a 66.7% efficacy rate and nearly 12 months of progression-free survival (PFS). These data are quite remarkable in the first-line HER2-targeted treatment field (2024 ESMO Abstract 1297P). Whether these small molecule TKIs will be moved to first-line treatment like DS8201 remains to be seen.
Oncology Frontier: Since the number of lung cancer patients with rare mutations is relatively small, and patient enrollment is more difficult, could you discuss how to address the research challenges related to these gene variations?
Dr. Yan Wang: For targeted therapies against rare targets, future efforts need to focus on precisely selecting patient populations to achieve higher efficacy, exploring resistance mechanisms, and overcoming resistance with treatment strategies. Moreover, can we, as with EGFR-sensitive mutations, develop targeted therapies that successfully treat late-stage patients and then move them to perioperative treatment stages? These are important research directions.
Because the occurrence of rare mutations is indeed very low, patient enrollment is challenging, and conducting randomized controlled Phase III clinical studies is difficult. This requires collaborative efforts from industry professionals nationwide and globally to pool patients with rare mutations for clinical research. Additionally, we could build shared data platforms to establish a more solid evidence base.
Dr. Yan Wang
Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences
Chief Physician, Doctoral Supervisor
Member of the Lung Cancer Professional Committee, Chinese Anti-Cancer Association
Director of the Chinese Society of Clinical Oncology
Chairman of the Translational Medicine Subcommittee, Beijing Cancer Prevention and Treatment Research Association
Vice Chairman of the Lung Cancer Professional Committee, Beijing Anti-Cancer Association
Vice Chairman of the Lung Cancer Immunotherapy Professional Committee, Beijing Cancer Prevention Association
Vice Chairman of the Lung Cancer Professional Committee, Beijing Oncology Society
Standing Committee Member of the Drug Adverse Reaction Management Subcommittee, Beijing Cancer Prevention and Treatment Research Association
Editorial Board Member of Chinese Journal of Lung Cancer and Chinese Journal of the British Medical Journal
