Editor’s Note:
The 2023 European Society for Medical Oncology (ESMO) Annual Meeting took place in Madrid, Spain, from October 20th to 24th. The Tumor Insight team delved into the front lines, capturing international advancements and witnessing China's contributions to the field of oncology on the global stage. Professor Cai-Cun Zhou from Tongji University Affiliated Shanghai Pulmonary Hospital delivered an important oral presentation at this conference (Abstract No: LBA33). In a live interview with "Tumor Insight," Professor Zhou shared insights into the research on the novel KRAS G12D inhibitor HRS-4642 for the treatment of late-stage solid tumor patients with KRAS G12D mutation, as well as thoughts and perspectives on the future direction of drug development. This article summarizes the relevant content for readers.
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Oncology Frontier : KRAS mutations are crucial oncogenic drivers, and due to their structural complexities, they have long been considered challenging targets for drug development. Currently approved drugs primarily target the G12C mutation, and HRS-4642 is the world’s first innovative drug developed in China that targets KRAS G12D. Could you please introduce the characteristics of the KRAS G12D target, as well as the background and motivation behind this research?
Professor Cai-Cun Zhou:KRAS was the first oncogenic driver gene discovered, dating back quite some time. However, it wasn’t until the past two years that we had drugs targeting KRAS G12C, such as sotorasib and adagrasib, with response rates of 40% and a progression-free survival (PFS) of 6.5 months. Clearly, the efficacy is not satisfactory, and we are eagerly awaiting better drugs. There are many products in development in this field.
KRAS G12D is a significant sub-type of KRAS mutations, and drugs targeting this particular mutation have not been successful thus far. The major issue with oral G12C inhibitors is their low bioavailability, which makes them ineffective for tumors with KRAS G12D mutations. The KRAS G12D inhibitor HRS-4642 can be administered intravenously, overcoming the limitation of oral formulations. KRAS G12D is found in approximately 30% of pancreatic cancers, 12% of colorectal cancers, and 6% of lung cancers. Resolving the issue of KRAS G12D inhibitors could have a significant impact on the treatment of various cancers. Hengrui’s HRS-4642 is the first KRAS G12D inhibitor reported at an international conference. Research on HRS-4642 is ongoing, and we hope to complete the data as soon as possible and make HRS-4642 available to patients worldwide, offering them more treatment options.
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Oncology Frontier: Could you please introduce the main results of this study, including efficacy and safety data, and what guidance these findings offer for further confirmatory research?
Professor Cai-Cun Zhou: In this study, we presented the preliminary results of HRS-4642 in its first human trial. Eighteen patients with KRAS G12D or G12V mutations participated in the clinical research. We employed an accelerated titration method with a Bayesian optimal interval (BOIN) design and have escalated the dosage to 300 mg once a week. The patients enrolled in this Phase I clinical study primarily had tumors like non-small cell lung cancer, pancreatic cancer, and colorectal cancer. During the dose escalation, one lung cancer patient treated with the G12D inhibitor HRS-4642 showed a significant reduction in tumor size, achieving a partial response (PR). The disease control rate (DCR) for non-small cell lung cancer reached approximately 90%, with more than half of the patients experiencing tumor shrinkage, which is quite encouraging. Therefore, we aim to enroll suitable patients as quickly as possible and expand the study with the appropriate dosage to validate the efficacy observed during dose escalation. So far, we haven’t observed dose-limiting toxicity (DLT). After receiving HRS-4642 treatment, some patients experienced hyperlipidemia, which is easily understandable since liposomes consist of triglycerides and cholesterol. However, other adverse reactions were relatively uncommon. In summary, HRS-4642 has shown tolerable safety and promising efficacy up to this point.
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Oncology Frontier: The FDA’s comprehensive analysis shows that KRAS mutation patients can benefit from immunotherapy combination therapy. Could you please discuss the role and significance of immunotherapy in the treatment of KRAS-mutated patients?
Professor Cai-Cun Zhou: Immunotherapy as a single agent or in combination with chemotherapy is the standard treatment for patients with high PD-L1 expression and KRAS mutations, and the efficacy is quite encouraging. However, we need to consider that KRAS mutations may be accompanied by STK11 or KEAP1 mutations, which often categorize the tumors as “cold tumors,” with suboptimal responses to single-agent immunotherapy or immunotherapy combined with chemotherapy. Enhancing the efficacy further is a challenge we face.
The first Phase I clinical trial of KRAS G12C inhibitors in combination with immunotherapy, specifically sotorasib in combination with atezolizumab or pembrolizumab, showed a high incidence of grade 3-4 hepatotoxicity, ranging from 20% to 90%. This outcome indicates that it is not suitable for clinical practice, and this approach has been ruled out. Roche and other pharmaceutical companies are also exploring the combination of KRAS G12C inhibitors with immunotherapy. In addition to the existing standard treatments of single-agent immunotherapy or immunotherapy combined with chemotherapy, the combination of KRAS inhibitors with immunotherapy and chemotherapy may become a new standard treatment for KRAS-mutated patients. This is the direction we are currently exploring.
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Oncology Frontier: Immunotherapy’s long tail effect has brought significant survival benefits to patients, with some achieving “clinical cures.” For example, in first-line treatment of non-squamous NSCLC with the combination of Carrelizumab and chemotherapy, the 4-year overall survival rate is 37.2%, with over one-third of patients surpassing the 4-year mark. Could you please discuss the clinical significance of the long-term survival benefits of immunotherapy?
Professor Cai-Cun Zhou: Immunotherapy is different from other treatments. For instance, with other treatments, if we can help patients live a few more months and improve their median survival, we are generally pleased. However, with immunotherapy, we aim to increase the cure rate, which is crucial for achieving long-term survival. International immunotherapy drugs like “K drugs” in combination with chemotherapy have shown 5-year survival rates of 18%, with some reaching as high as 32%. The 5-year survival rate for PD-L1 negative patients is 9% to 12%. The combination of Carrelizumab with chemotherapy has significantly improved overall survival (OS) for squamous and non-squamous NSCLC patients, with median OS exceeding 27 months, surpassing other products. The 4-year survival rate for immunotherapy in combination with chemotherapy is consistently above 37%. In the CameL study, the 3-year and 4-year survival rates for non-squamous NSCLC were 39.3% and 37.2%, with only a 2% decline in one year. We are now eagerly awaiting the 5-year survival rate, and if it remains at 35% or only decreases by 2% from the 4-year rate, it will undoubtedly be the highest among similar studies. Domestic PD1/PD-L1 inhibitors like IBI®️ are effective in combination with chemotherapy. IBI®️ in combination with chemotherapy enables one-third of patients to live beyond four years, and even five years, which is highly encouraging. We look forward to the release of the 5-year survival data from the CameL study.
In January 2023, the pivotal CameL study, a randomized, open-label, multicenter, Phase III trial, compared Carrelizumab in combination with carboplatin and pemetrexed to first-line treatment with chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC) without driver gene mutations. The study reported long-term follow-up data at 4 years (with a minimum follow-up duration of 43.9 months) in the JTO journal. Carrelizumab in combination with chemotherapy significantly extended the median overall survival (mOS) by 7.3 months (27.1 vs. 19.8 months), reducing the risk of death by 28% (HR 0.72, 95% CI: 0.57–0.92, P=0.0038). The 3-year and 4-year overall survival rates for the Carrelizumab in combination with chemotherapy group were 39.3% (compared to 30.4% in the chemotherapy group) and 37.2% (compared to 25.6% in the chemotherapy group), respectively.
In the 2022 ELCC conference, the 3-year follow-up data of the multicenter, randomized, placebo-controlled, double-blind Phase III CameL-sq study were presented. The study compared Carrelizumab in combination with chemotherapy to placebo in combination with chemotherapy for first-line treatment of advanced lung squamous cell carcinoma. Carrelizumab in combination with chemotherapy extended the median overall survival (mOS) by nearly one year (27.4 vs. 15.5 months), significantly reducing the risk of death by 43% (HR 0.57, 95% CI: 0.44–0.74; P<0.0001). The 3-year overall survival rate for the Carrelizumab in combination with chemotherapy group was 42.8% (compared to 23.7% in the placebo in combination with chemotherapy group), demonstrating the potent long-tail effect of the strong PD-1 inhibitor and providing more squamous NSCLC patients with extended survival.
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Oncology Frontier: In recent years, Chinese innovative drugs, represented by Hengrui, have announced numerous research achievements on various international stages, showcasing the prowess of Chinese scholars and Chinese pharmaceuticals. Could you please share your views on the current state of original drug research and development in China and your expectations for the future?
Professor Cai-Cun Zhou: After nearly 20 years of accumulation, in recent years, Chinese pharmaceutical companies have produced more “first in class” and “best in class” products. This has provided Chinese experts with more opportunities to grow alongside the development of Chinese pharmaceutical companies, gradually enabling Chinese experts to step onto the world stage. This is a positive development. We have seen many excellent products and published numerous quality research papers, achieving noteworthy results. However, we should not become complacent. There is still a gap between Chinese pharmaceutical companies and foreign counterparts. We must continue down the path of innovation.
We hope that domestic pharmaceutical companies can succeed in areas such as the development of the first-in-class products, targeting rare or challenging molecular targets, and discovering new targets. We hope that our pharmaceutical companies can become global industry leaders. In the case of KRAS G12D, China’s leading pharmaceutical company, Hengrui, has succeeded. We hope that Hengrui can increase its investment in translational research, establish its position in the discovery of new targets, approved drugs for challenging targets, and contribute even more. We wish Hengrui continued success and growth!
