EGFR mutations other than 19Del and L858R are called uncommon mutations and account for ~10% of all EGFR mutations. 1,2 These mutations have almost identified 600 variants, and represent a highly heterogeneous group with distinct clinical features. 3,4 Being excluded from most prospective clinical trials, the evidence for EGFR uncommon mutations have been mainly derived from retrospective studies or combined post-hoc analysis of trials with limited sample size due to the rarity of this setting. [5][6][7] Only two small-scale studies have prospectively evaluated the efficacy of EGFR-TKIs for uncommon mutations. Osimertinib demonstrated activity with an ORR of
Purpose: For patients with advanced nonsquamous non-small cell lung cancer (NSCLC), immunotherapy or antiangiogenic therapy combined with pemetrexed and cisplatin/carboplatin have both shown significant efficacy at programmed cell death ligand 1 (PD-L1) levels of <1%. Our study aimed to compare two firstline regimens for patients with advanced nonsquamous NSCLC who were negative for PD-L1.Methods: A retrospective cohort study was conducted comparing the outcomes of patients with advanced PD-L1(-) nonsquamous NSCLC who were treated with antiangiogenic therapy plus chemotherapy (A Group) to those who were treated with anti-PD-L1 monoclonal antibodies plus chemotherapy (mAbs) (B Group).Both regimens were evaluated for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and side effects.Results: 114 patients were enrolled in the study, 82 in Group A and 32 in Group B. Those in Group A had a longer median PFS (9.8 vs. 6.7 months, p = 0.025). The OS was also achieved (p = 0.058). No statistically significant difference was seen in ORR (52.4% vs. 50.0%, p = 0.815) or DCR (93.9% vs. 87.5%, p = 0.225) between the two groups. Patients in the A group who did not smoke and did not have specific metastases could benefit from survival. Adverse events (AEs) in both groups were tolerated. Conclusion:Bevacizumab plus chemotherapy outperformed immunotherapy plus chemotherapy in terms of PFS.
e20611 Background: The IMpower 133 trial represents the current SoC in the 1L setting for pts with ES-SCLC but still needs further efficacy improvement such as objective response rate (ORR, ̃60% in both arms) which may lead to survival benefit. LDRT could play a key role in the priming effect of immune system by acting as an immune adjuvant and having sensitive cytotoxic activity to SCLC. We have reported that LDRT plus ICIs in pretreated ES-SCLC was well tolerated with an improved efficacy. Here we conducted MATCH study to investigate the clinical benefits of adding LDRT to Atezo plus chemotherapy in ES-SCLC pts as 1L therapy. Methods: The MATCH study was a single-arm phase II trial conducted in eight centers across China. A Simon’s minimax two-stage design was adopted. Pts with measurable disease per RECIST v1.1 at baseline with ECOG 0-1 were eligible. Atezo (1200 mg IV, D1) + Cisplatin (75 mg/m2 IV, D1)/Carboplatin (AUC = 5 IV, D1) +Etoposide (100 mg/m2 IV, D1-D3) were administrated on a 21-day cycle for four cycles. Concurrent LDRT (15 Gy/5f) were conducted from D1-D5 in the first cycle. Then pts received Atezo maintenance until loss of clinical benefit or unacceptable toxicity. The primary endpoint was ORR confirmed by investigators after two consecutive evaluations ≥ 4 weeks apart. The secondary endpoints included disease control rate (DCR) and safety. Results: This is the report on the completed 1st phase of the trial. By the cutoff date of 26th August 2021, of the first 21 evaluable pts, 20 were males; mean age was 60.2 y and 85.7% pts had ECOG PS of 1. Previous smokers were 85.7%. Most pts were staged T4 (n = 15, 71.4%), N3 (n = 18, 85,7%) and M1(n = 17, 81.0%). The most common sites of metastasis were bone (47.1%) and liver (11.8%). Median follow-up was 4.0 m (range: 2.6-8.0 m). The confirmed ORR was 95.2% (95% CI, 76.2%-99.9%), among whom all pts were PR. DCR was 100%. The safety profile was consistent with the previous reports. Neutrophil count decreased (66.7%), white blood cell count decreased (42.9%) and anaemia (38.1%) were the most common grade 3-4 adverse events. No grade 5 AE occurred. Two pts experienced AEs leading to treatment withdrawal. IrAEs by preferred term were reported in 3(14.3%) pts: 2 were immune-mediated hyperthyroidism (grade 2) and 1 was immune-mediated enterocolitis (grade 3). No radiation pneumonitis occurred. Conclusions: The study met the response criteria for 1st phase. The combination of LDRT and Atezo plus chemotherapy showed promising benefit and was tolerable in pts with ES-SCLC. The 2nd phase is ongoing. Clinical trial information: NCT04622228.
Purpose:Low-dose radiation therapy (LDRT) may enhance the synergistic anti-tumor effect of combined immunotherapy and stereotactic body radiation therapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). Patients and Methods:This prospective phase 1 study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT (30 Gy/3f) to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a PD-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results:No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAEs) occurred in 96.6% (28/29) of patients (grade ≥ 3, 20.7% [6/29]); two patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval 3.7–16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging TCR clonotypes were associated with better PFS. Conclusions:The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with PD-L1-positive, driver gene-negative primary metastatic NSCLC.
Background: The IMpower133 represented the current standard of care in the 1L setting for patients (pts) with ES-SCLC (extensive-stage small cell lung cancer). However, there are still unmet needs for ES-SCLC treatment. LDRT could play a key role in the priming effect of immune system by acting as an immune adjuvant and having sensitive cytotoxic activity to SCLC. The interim analysis of MATCH study after stage I showed promising benefit and tolerability of combination of Atezo + chemotherapy + LDRT in pts with ES-SCLC. Here we report the primary efficacy and safety results of this study. Methods: The MATCH study was a single-arm phase II trial conducted in 8 centers across China. Previously untreated ES-SCLC pts with measureable disease per RECIST v1.1 at baseline, age≥18, ECOG 0-1 were eligible. Atezo (1200 mg IV, D1) + Cisplatin (75 mg/m2 IV, D1)/Carboplatin (AUC = 5 IV, D1) +Etoposide (100 mg/m2 IV, D1-D3) were administrated on a 21-day cycle for four cycles. Concurrent LDRT (15 Gy/5f) were conducted from D1-D5 in the first cycle. Then pts received Atezo maintenance until loss of clinical benefit or unacceptable toxicity. The primary endpoint was objective response rate (ORR), defined as the proportion of patients with a complete response or partial response on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. A Simon’s minimax 2-stage design was adopted. Results: As the cutoff date of 30th Nov. 2022, 56 pts have been enrolled. 49 (87.5%) were males; mean age was 58.9 years with 78.6% pts had ECOG PS of 1. 80.4% pts had smoking history. Most pts were staged T4 (n = 33, 58.9%), N3 (n = 37, 66.1%) and M1(n = 40, 71.4%). Median follow-up was 14.8 months (range: 11.6-17.8 m). The confirmed ORR was 87.5% (95% CI: 75.9%-94.8%), all partial response. DCR was 94.6% (95% CI: 85.1%-98.9%). Median PFS was 6.9 m (95% CI: 5.4-9.3 m). The 6-month and 12-month PFS rate were 56.5% and 27.7%. Median OS was not reached (NR, 95% CI: 13.3m, NR). The 12-month OS rate was 71.9%. The safety profile, analyzed in all 56 pts, was consistent with the previous reports. Neutrophil count decreased (60.7%), white blood cell count decreased (58.9%) and platelet count decreased (23.2%) were the most common grade (G) 3-4 adverse events (AE). G5 AE occurred in 1 pt (pneumonia and pulmonary embolism). 4 pts experienced AEs leading to treatment discontinuation. IrAEs were reported in 21 (37.5%) pts, most common irAEs were hyperthyroidism (5.4%) and rash (5.4%). Radiation pneumonitis (G1) was observed in 1 pt. Conclusions: Adding LDRT to Atezo + chemotherapy shows impressive antitumor activity, potential survival benefit and well tolerability in 1L treatment of ES-SCLC. Clinical registration: NCT04622228. Citation Format: Lin Zhou, Jianguo Sun, Conghua Xie, Youling Gong, Meijuan Huang, Zhiyong Yuan, Lin Wu, Hui Wang, Nan Bi, Yaping Xu, Jiang Zhu, Yongmei Liu, Yan Zhang, Min Fan, Bingwen Zou, Min Yu, Yanying Li, Feifei Na, Weigang Xiu, Yong Xu, Jin Wang, Xuanwei Zhang, Jianxin Xue, You Lu. Efficacy and safety of Low dose radiotherapy (LDRT) concurrent Atezolizumab (Atezo) plus chemotherapy as first line (1L) therapy for ES-SCLC: Primary analysis of Phase II MATCH study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT219.
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