Dr. Shi Meiqi

Department of Medical Oncology, Lung Cancer Subspecialty

Jiangsu Cancer Hospital/Jiangsu Institute of Cancer Research

Introduction:

The 2023 World Lung Cancer Congress (WCLC) took place at the Singapore Expo Center from September 9th to 12th. Dr. Shi Meiqi from Jiangsu Cancer Hospital presented crucial findings in a phase 1/2 clinical study at this conference (MA15.09). In an interview with ” Oncology Frontier ,” Dr. Shi Meiqi shared research insights, key results, and treatment strategies for KRAS mutation non-small cell lung cancer patients.

Dr. Shi Meiqi’s Insights:

WCLC serves as an essential platform for academic exchange in the field of lung cancer. This year, I had the privilege of presenting a Phase I/II study (ChiCTR1900026273) on TQ-B2450 in combination with anlotinib for EGFR-positive advanced NSCLC patients who had previously failed EGFR-TKIs. This conference provided me with the opportunity to share our research’s background and major results. WCLC means a lot to me , and to every thoracic oncologist.

Over the past two decades, targeted therapy has significantly improved the effect in treating EGFR mutation-positive NSCLC patients. However, with the development of targeted therapy, we’ve encountered a new challenge: what treatment should we  offer when patients’ disease progresses after using all available targeted drugs.

EGFR mutation advanced NSCLC is notably higher among Asian populations than Western populations. After nearly 20 years of development, we now have first-generation, second-generation, and third-generation targeted drugs for EGFR mutations. Targeted therapy has brought significant therapeutic advancements, with doubled or even tripled efficacy compared to traditional chemotherapy. Whereas, in the era of chemotherapy, the median overall survival (OS) for advanced NSCLC patients was only around one year, targeted therapy has transformed these patients into those who can live for eight or even ten years, effectively turning NSCLC into a chronic disease.

However, as targeted therapy has advanced, we’ve faced a bottleneck. When all available targeted drugs have been exhausted and patients experience disease progression, what should be the subsequent treatment? Up to this point, major guidelines and expert consensus still primarily recommend chemotherapy or chemotherapy combined with anti-angiogenic agents after EGFR-TKIs resistance. Over the past decade, there has been extensive research in immunotherapy for this patient population, especially after EGFR-TKIs resistance. However, early studies on both single-agent immunotherapy and immunotherapy combined with EGFR-TKIs didn’t demonstrate significant efficacy and, in some cases, even increased toxicities. The studies on immunotherapy combined with chemotherapy have also produced mixed results.

Notably, in the IMpower 150 study, approximately 10% of EGFR-TKIs-resistant patients were enrolled, showing favorable outcomes with a four-drug combination of immunotherapy, chemotherapy, and bevacizumab for EGFR-TKIs-resistant patients. Last year, the ORIENT-31 study reported positive results for the four-drug combination therapy in Chinese patients with EGFR-TKIs resistance.

Our National Medical Products Administration has also approved this four-drug combination therapy for EGFR-TKIs-resistant patients. However, in clinical practice, many patients are reluctant to undergo chemotherapy, and some even refuse it. While guidelines recommend retesting for resistance mutations after EGFR-TKIs resistance and tailoring subsequent targeted therapy based on the results, not all patients can identify resistance mutations or obtain tissue samples for testing. In these cases, chemotherapy-based treatment becomes the only option.

Now, the four-drug combination is one of the recommended standard treatment regimens in guidelines. However, many patients are hesitant about chemotherapy, and some cannot tolerate it. Frequently, dose reductions or modifications are necessary. This raises the question of whether these patients can still achieve the same level of efficacy as the standard regimen. At the 2023 ASCO conference, real-world studies on the four-drug combination showed that only 20% of EGFR-TKIs-resistant patients met the inclusion criteria. Many patients could not tolerate the standard four-drug combination due to various health reasons, resulting in less-than-optimal efficacy.

At the 2019 WCLC conference, Sintilimab + Anlotinib as first-line treatment for driver gene-negative advanced NSCLC patients showed impressive results. Although the sample size was small, the overall response rate (ORR) reached 70%, and 1-year progression-free survival (PFS) exceeded 90%, demonstrating significant advantages over the standard immunotherapy combined with chemotherapy regimen. In Chinese lung adenocarcinoma patients, more than half have driver gene mutations. While single-agent immunotherapy is ineffective for these patients, the combination of immunotherapy and Anlotinib might yield positive results. We have designed a small-sample clinical study to explore this treatment.

Following discussions with CTTQ pharma (TQ-B2450’s manufacturer), we conducted a Phase I/II clinical trail of TQ-B2450 (PD-L1 inhibitor) combined Anlotinib for EGFR-TKIs-resistant advanced NSCLC patients. A total of 64 patients were enrolled, with 9 in Phase I and 55 in Phase II. This study was conducted from December 2019 to October 2022, despite the challenges posed by the COVID-19 pandemic, which led to treatment delays and interruptions for some patients. Nonetheless, with the joint efforts of the study participants, the study was successfully completed. Currently, nearly 10 patients are still under treatment, and the longest treatment duration among our patients has exceeded 3 years. The results of this study show a median PFS of nearly 9 months, which is not inferior to many clinical research results from similar studies. The treatment regimen is simple and convenient, with overall good tolerability. Since it involves discontinuation of chemotherapy, it ensures that patients have a good physical condition for subsequent treatment, providing many opportunities for post-resistance treatment, such as chemotherapy and the challenge of previously used targeted drugs. The median overall survival (OS) in our study exceeded 28 months, indicating the long-term advantages of this treatment strategy. This study, due to its small sample size, cannot yet be considered high-level evidence for clinical application but is worth considering. It provides confidence and reference for further research with larger sample sizes.

Regarding KRAS mutations, they have been challenging to target effectively. Sotorasib and adagrasib have shown promise in later-line treatment, but further research is needed to determine their optimal use. Immunotherapy and immunotherapy combined with chemotherapy have shown promise for KRAS mutation patients. However, combining KRAS g12c-targeted therapy with immunotherapy may face challenges due to increased toxicity.

In conclusion, while the treatment landscape for lung cancer is evolving, there is still much research to be done to determine the best treatment strategies for different patient populations.