Editor’s Note:
The 2023 World Conference on Lung Cancer (WCLC), held from September 9th to 12th at the Singapore, provided a platform for oncology experts to delve into cutting-edge developments. The “Oncology Frontier” team reports on-the-spot international cutting-edge developments and witnesses the progress of China’s anti-cancer cause on the international stage. Renowned oncologist Dr. Baohui Han, from the Shanghai Chest Hospital, delivered a significant address at the conference. In an exclusive interview with “Oncology Frontier”, Dr. Han shared profound insights into the latest breakthroughs and contemplations on hot topics in targeted therapy for lung cancer.
Dr. Baohui Han
Shanghai Chest Hospital
01
Oncology Frontier: The 2023 World Conference on Lung Cancer showcased myriad breakthroughs in the realm of targeted therapy for lung cancer. As a luminary in China’s lung cancer domain, could you illuminate us on the standout developments that left a lasting impression at this prestigious gathering?
Professor Han Baohui: The recently concluded World Conference on Lung Cancer in Singapore witnessed a grand convergence of over 6,000 experts spearheading lung cancer research globally. This assembly divulged the latest strides in translational and clinical research, featuring over 300 scholarly presentations and thousands of poster exhibitions. Advancements in targeted therapy, immunotherapy, and multidisciplinary comprehensive treatment took center stage, addressing challenges such as rare mutations, post-resistance targeted therapy, and sequential local consolidation therapy.
The saga of targeted therapy commenced with the clinical application of EGFR signaling pathway inhibitors in 2003, and two decades later, the exploration continues. We delved into aspects like rare mutations of EGFR, resistance mutations, and integrating immunotherapy post first-line treatment failure. These explorations significantly augment the efficacy of targeted therapy. Addressing the therapeutic dilemma posed by EGFR exon 20 insertion mutations, our team presented updated research results on the use of domestically produced third-generation EGFR-TKIs [1] (Abstract: OA03.04). This novel class demonstrated remarkable efficacy, broadening treatment options for EGFR 20INS mutation patients within China.
However, targeted therapy may encounter resistance. EGFR, ALK, ROS1, MET, and BRAF-positive NSCLC invariably develop resistance post targeted therapy. Resistance remains a perennial theme and an unavoidable clinical challenge. It may arise from on-site mutations or bypass activation under selective pressure, necessitating a meticulous categorization and control strategy. Biopsy, with tissue biopsy as the gold standard and liquid biopsy as a complementary tool, becomes imperative. Tailoring subsequent treatment plans based on resistance types becomes crucial. Our study [2] (BGB-A317-2001-IIT study) revealed that for patients resistant to EGFR-TKIs, with unknown resistance mechanisms, no other targetable points, and tolerable conditions, a non-platinum regimen (single-agent chemotherapy + camrelizumab + PD1 inhibitor) proves to be a viable choice, yielding commendable efficacy.
Beyond advancements in treating lung cancer patients resistant to targeted therapy, there have been notable strides in studies focusing on sequential local treatments post targeted therapy. For instance, our team’s recent study [3] published in “Lung Cancer” highlighted that EGFR-mutant patients benefiting from sequential local treatment post targeted therapy exhibited a significant improvement in overall survival. This underscores the potential benefits of adding local treatments like percutaneous cryoablation, SBRT, or surgery to targeted therapy in patients with EGFR mutations and concurrent bone oligometastasis. The results demonstrated a markedly improved prognosis compared to systemic therapy alone, with a median overall survival of 36 months for the sequential local treatment group and approximately 24 months for the systemic therapy alone group—a notable increase in median overall survival.
Similarly, ALK-mutant patients experienced enhanced disease control following sequential local treatment. The BRIGHTSTAR trial [4] (Abstract: OA22.04) unveiled during this year’s WCLC assessed the safety and efficacy of local consolidative therapy (LCT) with brigatinib after induction with brigatinib. The 3-year progression-free survival (PFS) for the group receiving LCT after brigatinib induction stood at 66%, while the group receiving brigatinib alone exhibited a 3-year PFS of 47%, signifying a significant difference between the two cohorts. The positive outcomes from the BRIGHTSTAR trial once again affirmed that local treatment following systemic therapy could offer substantial survival benefits to metastatic NSCLC patients, compared to systemic treatment alone.
Deciding on the implementation of sequential local treatment after systemic therapy hinges on the assessment of the current intensity of targeted therapy and the depth of tumor remission. If the treatment intensity and tumor remission depth fall short, indicating untapped potential, then implementing sequential local treatment on the foundation of targeted therapy becomes a viable strategy to enhance tumor remission depth and treatment intensity—potentially providing significant assistance in improving overall patient survival. In the BRIGHTSTAR study, the use of local treatment after brigatinib induction significantly increased the local control rate, reducing the likelihood of developing resistant tumor cell lines. This may translate the PFS advantage into an overall survival advantage, potentially prolonging the patient’s life.
02
Oncology Frontier: Personalized treatment stands as the cornerstone of lung cancer therapeutic evolution. In the realm of targeted therapy for lung cancer, can higher-than-usual doses or combinations with other treatments be deployed to enhance efficacy for patients with a high tumor burden or brain metastases?
Professor Han Baohui: This facet indeed warrants collective attention and exploration. Brain metastasis emerges as the pivotal factor curtailing overall survival among all extrapulmonary organs affected by lung cancer. Effective control of brain metastasis proves indispensable for a significant improvement in overall survival.
Targeted therapy boasts a distinctive feature—a broad
therapeutic window. Should a patient present with special circumstances, such as the existence of brain metastasis, a substantial tumor burden, or concurrent malignancies, increasing the dosage can undoubtedly be considered under conditions that ensure safety. Alternatively, to augment local control rates, especially for brain metastasis, combination therapies involving drugs like bevacizumab can be explored.
Research Overview: OA22.04-BRIGHTSTAR Local Consolidative Therapy with Brigatinib in Tyrosine Kinase Inhibitor-Naive ALK-Rearranged Metastatic NSCLC
▍Background
Approximately 95% of ALK-TKI initial responders exhibit incomplete remission, leading to residual lesions and eventual acquired resistance. LCT aims to minimize or eliminate residual lesions, potentially delaying resistance and improving clinical outcomes.
▍Methods
The BRIGHTSTAR trial is a single-center clinical trial initiated by researchers from MD Anderson Cancer Center, aiming to assess the safety and efficacy of LCT after brigatinib induction. The study included TKI-naive patients with oligometastatic or polymetastatic ALK-positive NSCLC. Patients underwent brigatinib induction treatment for 8 weeks, followed by LCT with radiation therapy and/or surgery. Imaging assessments were performed on patients at baseline and after brigatinib induction, with tumor burden defined by overall 3D tumor volume. Additionally, the study retrospectively analyzed data from the Phase III ALTA-1L trial.
▍Results
34 patients were enrolled in the study, with a median age of 56 years (range 33–73 years). At baseline assessment, 82% (n=28) of patients had polymetastatic disease (>3 lesions), and 41% (n=14) had brain metastases.
After brigatinib induction treatment, 94% (32/34) of patients were eligible for LCT, including radiation therapy (n=27), surgery (n=3), and surgery + radiation therapy (n=2). Two patients did not undergo LCT (1 withdrew consent, 1 had no suitable lesions for LCT). Among the five patients who underwent surgery, surgical procedures included lobectomy in four cases, sublobar resection in one case, and adrenalectomy in one case. Postoperative specimen analysis of the five patients revealed complete pathological responses in two patients, with one achieving complete pathological response in the primary lesion. Four patients (12%) experienced grade ≥3 LCT-related adverse events (LRAEs), including grade 4 bronchopulmonary hemorrhage (n=1), grade 3 pneumonia (n=1), grade 3 anemia (n=1), grade 3 nausea (n=1), grade 3 vomiting (n=1), and grade 3 esophagitis (n=1).
After 8 weeks of brigatinib induction treatment, the disease control rate was 100%, and the objective response rate was 79% (n=27). The 1-year, 2-year, and 3-year PFS rates for the brigatinib + LCT group were 94%, 80%, and 66%, respectively. In contrast, the ALTA-1L study reported 1-year, 2-year, and 3-year PFS rates of 76%, 56%, and 47%, respectively, for patients who did not progress within 12 weeks of brigatinib treatment.
In the BRIGHTSTAR study, among the 12 patients with disease progression (PD), when data analysis was conducted, the brain was the sole site of PD in 6 patients (50%). Univariate Cox model analysis showed that baseline ALK mutation and the number of metastatic sites could not predict PFS. Lower tumor burden at baseline and after induction treatment was associated with better PFS (HR=1.006, P=0.007).
Conclusion
Brigatinib induction followed by LCT in advanced ALK-positive NSCLC patients showed good safety and, compared to using brigatinib alone, the use of LCT after brigatinib induction delayed resistance, reduced tumor burden, and improved clinical outcomes. The reduction in tumor volume after brigatinib induction treatment, as well as LCT for all lesions, was associated with better clinical benefits, benefiting both oligometastatic and polymetastatic patients from the use of LCT after brigatinib induction treatment.
References
[1] OA03.04 A Phase 1b Study Of Furmonertinib, an Oral, Brain Penetrant, Selective EGFR Inhibitor, in Patients with Advanced NSCLC with EGFR Exon 20 Insertions，2023 WCLC.
[2] 136P Tislelizumab (TIS) plus chemotherapy (chemo) for EGFR-mutated non-squamous non-small cell lung cancer (nsq-NSCLC) failed to EGFR tyrosine kinase inhibitors (TKIs) therapies: The primary analysis，2022 ESMO IO. DOI:https://doi.org/10.1016/j.iotech.2022.100248
[3] HU F, LI C, XU J, et al. Additional local consolidative therapy has survival benefit over EGFR tyrosine kinase inhibitors alone in bone oligometastatic lung adenocarcinoma patients [J]. Lung Cancer, 2019, 135: 138-44.
[4] OA22.04-BRIGHTSTAR Local Consolidative Therapy with Brigatinib in Tyrosine Kinase Inhibitor-Naïve ALK-Rearranged Metastatic NSCLC，2023 WCLC.
TAG: WCLC 2023, Interview, Targeted Therapy
