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China Studies Featured in Nature!
Written by | Zhang Rongxin
In recent years, immunotherapy has been used as the standard first-line treatment for advanced squamous non-small cell lung cancer (sq-NSCLC), bringing clinical benefits to patients. However, the optimal model of immunotherapy needs to be further explored: previous studies have shown that monotherapy or dual immunotherapy (without chemotherapy) is less effective in the early stages, while standard chemotherapy (4-6 cycles) combined with immunotherapy can confer survival benefits, but safety concerns remain unresolved.
Recently, Nature Communications published a phase II clinical study on sintilimab combined with short-course chemotherapy in the first-line treatment of sq-NSCLC, which is expected to provide a new treatment mode for sq-NSCLC immunotherapy combined with chemotherapy. In this issue of "Researchers Say", Professor Wang Huijuan, the corresponding author of the paper, Professor Ji Yinghua, a research expert, and Dr. Zhang Mina, the first author, are invited to conduct an in-depth discussion on the latest research results.
The dose of chemotherapy was reduced without reducing the effect, and the median PFS was 11.4 months!
"In the era of chemotherapy, the treatment of sq-NSCLC is often based on the standard chemotherapy regimen of 4-6 cycles, and in the era of immunotherapy, although immunotherapy and chemotherapy have a synergistic effect, high-intensity chemotherapy will kill immune cells and affect the immune function of the patient's body, so the team explored the efficacy and safety of the immunotherapy combined with short-course chemotherapy regimen." ”
Forty-eight patients with sq-NSCLC from six clinical centers in Henan Province were included in the study who received a short course of chemotherapy [nab-paclitaxel (260 mg/m2) + carboplatin (AUC=5), intravenous infusion, once every 3 weeks, 2 cycles] combined with sintilimab (100 mg/10 ml, 200 mg), followed by maintenance therapy with sintilimab. The primary endpoint is progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety.
Efficacy results
At a median follow-up of 24.2 months, the study met its primary endpoint, with a median PFS of 11.4 months (95% CI, 6.7 months-18.1 months) and a projected 12-month PFS rate of 42.9% (95% CI, 27.9%-57.1%) and 25.1% (95% CI, 11.7%-40.9%), respectively.
In terms of secondary endpoints, the ORR was 70.5% (95% CI, 54.8%-83.2%), all partial response (PR);D CR was 93.2% (95% CI, 81.3%-98.6%), the median DoR was 13.6 months (95% CI, 7.0 months-NE), the median OS was 27.2 months (95% CI, 20.2 months-NE), and the 12-month OS rate and 24-month OS rate were 79.1% (95%) CI, 63.6% to 88.5%) and 53.3% (95% CI, 35.5% to 68.2%).
Prof. Wang Huijuan said that the median PFS was 6.3 months to 8.5 months and the ORR was 49.7%-72.5%, based on previous studies using standard dose chemotherapy (4 cycles to 6 cycles) combined with immunotherapy (KEYNOTE-407, IMpower131, Camel-sq, RATIONALE-307) This revealed that the efficacy of short-course chemotherapy combined with immunotherapy is comparable to that of standard chemotherapy, and can improve the immune response at an early stage, bringing good clinical benefits.
Security results
In terms of safety, treatment-related adverse events (TRAEs) occurred in 91.3 percent, with the most common TRAEs including anemia (32.6 percent), elevated α-hydroxybutyrate dehydrogenase (28.3 percent), and alanine aminotransferase (26.1 percent). The incidence of grade ≥3 TRAEs was 10.9%, including decreased white blood cell count, immune-associated pneumonia, and rash. Two patients (4.3%) discontinued treatment due to TRAE, and no deaths due to TRAE were reported.
Prof. Wang added, "The current phase III clinical study of immunotherapy combined with standard chemotherapy (4-6 cycles) has an incidence of ≥ grade 3 TRAE of about 30%, compared with the safety data of this study. ”
Exploratory analysis
The study further explored the dominant population of immunotherapy combined with chemotherapy, and performed relevant analyses of biomarkers, plasma ctDNA changes and clearance, and the results showed:
First, the DoR was significantly longer in the PDL-1 TPS=1%-49% population compared to the PDL-1 TPS<1% and PDL-1 TPS≥50% subgroups. Professor Ji Yinghua said, "The results show that the beneficiary groups of immunotherapy combined with chemotherapy and immunomonotherapy are not completely consistent, and immune monotherapy has a better effect in patients with PDL-1 TPS ≥50%, but immunization combined with short-course chemotherapy is not completely positively correlated with the PDL-1 expression level of patients. ”
Second, patients with BRCA2, BRINP3, FBXW7, KIT, and RB1 mutations had a shorter median PFS compared with wild-type patients (22.1 versus 5.4 months; HR = 8.8, 95% CI: 2.4–32.0; P<0.001). This suggests that immunotherapy combined with chemotherapy is less likely to benefit patients with these mutated genes, and further exploration of treatment modalities for these patients is needed.
Third, ctDNA clearance is predictive. Patients who achieved ctDNA clearance in Cycle 1 or Cycle 2 had better outcomes than those who did not have ctDNA clearance. "These results will provide clinicians with timely assessment and early warning of patients' efficacy and drug resistance during treatment, which will help patients to individualize their care." ”
Two highlights to create an adaptive treatment plan suitable for the Chinese lung cancer population
The study met the primary endpoint in the pre-defined interim analysis with a manageable safety profile, providing new medical evidence for the treatment of SQ-NSCLC based on a short course of chemotherapy. In addition, the study has the following two highlights:
The study population is "China-specific", and the treatment regimen is "tailor-made"
Most of the study population was elderly (58.7% of patients ≥ 65 years old), males (97.8%), and smokers (80.4%), which met the main characteristics of lung squamous cell carcinoma patients in China.
Professor Ji Yinghua said that based on this baseline characteristic, the study cleverly designed the chemotherapy regimen, one is to choose the current clinical efficacy of nab-paclitaxel combined with carboplatin, and the other is to shorten the course of treatment, while initiating immune release and not inhibiting immunogenicity, enhance the anti-tumor activity of immunotherapy, and minimize the risk of adverse events.
The theme of the 2024 Lung Cancer Summit is adaptive therapy, that is, "addition" or "subtraction" based on the existing standard treatment regimen based on the patient's clinical characteristics, so that the treatment can be individualized. Professor Wang Huijuan believes that this study is precisely the response to the theme of this conference, breaking the treatment model of lung squamous cell carcinoma, "In the early stage of immunotherapy combined with chemotherapy, chemotherapy has a synergistic effect, however, after this period, its synergistic effect is not obvious, and the patient tolerance is not good, in the clinic, many patients to the 3rd-4th cycle of chemotherapy need to be reduced, therefore, this study is to do 'subtraction' for patients, by reducing the chemotherapy dose, it is expected to save economic costs, while reducing toxicity." ”
The tacit cooperation between doctors and patients, and the joint control of the main center and sub-centers, help the patient management to be refined
"In the face of various clinical situations, doctors need to have professional judgment ability, and they also need to fully communicate with patients who are under pressure, and mutual cooperation and trust between doctors and patients are the prerequisites for ensuring precise treatment. Dr. Zhang Mina took the patient with pseudo-progression of immunotherapy as an example: the patient's condition was stable in the early stage, but after 3-4 months of treatment, the tumor grew rapidly (less than 20%) but the density was low, after combining serum tumor markers and imaging manifestations, the team judged that it was a pseudo-progression in the process of immunotherapy, and after in-depth communication with the patient and relieving his psychological pressure, the original regimen was continued, and finally the patient's tumor shrank, proving that the treatment decision was correct.
In addition to the cooperation between doctors and patients, the refinement of patient management is also inseparable from the joint control of the main center and sub-centers. Professor Wang Huijuan said, "In addition to patient enrollment, when patients are unable to come to the main center due to personal reasons, the sub-center plays an important role in the process of patient conversion to ensure that every enrolled patient does not leave the group as much as possible, which also shows the enthusiasm and feelings of each researcher." ”
There are many challenges, and more exploration is still needed in the field of sq-NSCLC treatment in the future
Based on the positive results of this phase II study, Professor Wang Huijuan put forward her own ideas for the design of the phase III study: firstly, considering the excellent efficacy of bispecific antibodies in the field of lung cancer, can the combination of bispecific antibodies combined with chemotherapy consider a short-course treatment model? This phase II study only proves that it is feasible to do subtraction, and how to make this subtraction better, researchers need to open more innovative clinical studies in the future to continuously improve and enrich clinical practice. ”
In addition, for the treatment of advanced sq-NSCLC, Professor Wang Huijuan and Professor Ji Yinghua jointly put forward a series of problems and difficulties to be solved: in the future, how to screen patients with squamous cell carcinoma who are primary resistant to immunotherapy combined with chemotherapy and further explore their biomarkers? How to predict patients with acquired drug-resistant squamous cell carcinoma in advance? How to establish a clear classification model of lung cancer, or use organoids to predict clinical efficacy, so as to carry out precision treatment? High-quality clinical studies with more resources and better trial design to provide further answers.
To see more of the research, scan the QR code below to watch the live broadcast!
Expert Profile
Review experts: Professor Wang Huijuan, Professor Ji Yinghua, Dr. Zhang Mina
Editor in charge: Sheep
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