Combining a small molecule inhibitor of KRAS G12C with immune checkpoint blockade for first-line treatment of NSCLC
LBA4. Preliminary safety and efficacy of adagrasib with pembrolizumab in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation
Pasi Jänne (Harvard University, Boston, United States) presented preliminary results from studies investigating the safety and efficacy of adagrasib (ada) a small molecule inhibitor of KRAS G12C combined with pembrolizumab (pembro) in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) harboring the KRAS G12C driver mutation. In the KRYSTAL-1 Phase 1b cohort (n=7), four of seven patients exhibited a response lasting more than 9 months (median follow up of 19.3 mo), and two patients are still receiving therapy. Responding patients represented all levels of PD-L1 tumor levels. In the KRYSTAL-7 Phase 2 cohort (n=75; clinical evaluable population = 53), at a median follow-up of 3.5 months, the objective response rate was 49% (26/53), with one patient achieving a complete response, and disease control rate was 89% (47.53). Responses were observed across all PD-L1 patient subgroups, and response rate among patients with TPS>=50% was 59% (13/22). Treatment related adverse events (TRAEs) were observed in 83% of patients in the KRYSTAL-7 cohort, with no Grade 5 TRAEs. A KRAS G12C inhibitor in combination with an immune checkpoint inhibitor exhibits promising clinical activity and a manageable safety profile for first-line treatment of NSCLC harboring a KRAS G12C driver mutation across PD-L1 subgroups. These results support the planning of Phase 3 trials to compare ada + pembro to the current standard of care for first-line treatment of NSCLC.
Neoadjuvant therapy with SHR-1701, a bifunctional fusion protein targeting PD-1 and TGF-beta, for non-small cell lung cancer
LBA5. A phase 2 study of neoadjuvant SHR-1701 with or without chemotherapy (chemo) followed by surgery or radiotherapy
Yi-Long Yu (Guangdong Academy of Medical Sciences, Guangzhou, China) reported results from a Phase 2 trial investigating the effect of neoadjuvant SHR1701, a bifunctional fusion protein of monoclonal PD-1 antibody fused with the extracellular domain of TGF-beta receptor II, as monotherapy or in combination with chemotherapy (chemo) followed by surgery or radiotherapy (RT) for untreated stage III unresectable non-small cell lung cancer (uNSCLC). 107 patients enrolled in the study. Patients in Arm A (n=88; PD-L1 TPS < 50%) and Arm B (n=9; PD-L1 TPS > 50%) received induction treatment of SHR1701 with chemo, and patients in Arm C (n=10; TPS >50%) received induction treatment of SHR-1701 monotherapy. All treatment arms received surgery or definitive radiation therapy with chemotherapy, followed by adjuvant treatment with SHR-1701. 56.1% of patients achieved an objective response post-induction, and overall objective response rate (ORR) was 70.1%. Overall disease control rate (DCR) was 92.5%. ORR and DCR were consistently higher in patients receiving combination therapy (Arms A and B). Median event free survival (EFS) was 18.2 months. The surgical rate among patients was 25.2% (27/107), and among patients who received surgery, the major pathologic response rate was 44.4% (12/27), pathologic complete response rate was 25.9% (7/27), and 12-month event free survival rate was 74.4%. The safety profile of all three arms was manageable, with treatment related adverse events occurring in 99% of patients receiving combination therapy (Arms A and B) and 80% of patients receiving monotherapy (Arm C). Neoadjuvant SHR-1701 in combination with chemotherapy or as monotherapy followed by surgery or radiotherapy showed promising anti-tumor activity, and these data support further investigation of neoadjuvant SHR-1701 with chemotherapy for stage III uNSCLC.
Neoadjuvant immune checkpoint blockade combined with chemotherapy for non-small cell lung cancer
56O. A randomized, controlled, multicenter phase II trial of camrelizumab combined with albumin-bound paclitaxel and cisplatin as neoadjuvant treatment in resectable stage IIIA and IIIB(T3N2) non-small-cell lung cancer
Jie Lei (Tangdu Hospital, China) reported results from a Phase II trial investigating the efficacy of anti-PD-1 antibody camrelizumab (CAM) in combination with albumin-bound paclitaxel and platinum chemotherapy (CT) in the neoadjuvant setting for treatment of stage III resectable non-small cell lung cancer (NSCLC). 94 patients were enrolled in the study, and 88 patients received neoadjuvant treatment. In the experimental CAM+CT arm (n=42), 40 patients (85.1%) underwent surgery after neoadjuvant treatment, compared to 42 (91.3%) patients in the control CT arm (n=45). The pathologic complete response rate was significantly higher in the CAM+CT arm (32.6%), compared to the CT arm (8.9%). Major pathologic response rates were also significantly higher in the CAM+CT arm (65.1%) compared to the CT arm (15.6%). Event free survival and disease free survival rates are immature, but 24-month rates for the CAM+CT arm (76.9% and 78.4%) are higher than rates for the CT arm (67.6% and 71.7%). No new treatment-related adverse events were observed in the CAM+CT arm, with 25.6% of patients in the CAM+CT arm experiencing a treatment related adverse event >= Grade 3, compared to 11.1% in the CT arm. These results indicate that adding CAM to CT increases clinical efficacy of neoadjuvant treatment for NSCLC, and CAM combined with albumin-bound paclitaxel and cisplatin may provide a new neoadjuvant treatment option for patients with resectable NSCLC.
Post hoc analyses of adjuvant atezolizumab treatment and ctDNA status in patients with resected non-small cell lung cancer
1O: IMpower010: ctDNA status in patients (pts) with resected NSCLC who received adjuvant chemotherapy (chemo) followed by atezolizumab (atezo) or best supportive care (BSC)
Enriqueta Felip (Vall d’Hebron University Hospital, Barcelona, Spain) presented exploratory analyses of circulating tumor DNA (ctDNA) status of patients from the Phase III IMpower010 trial. The IMpower010 trial led to the approval of atezolizumab following adjuvant chemotherapy for resected non-small cell lung cancer. Previous analyses of IMpower010 indicate that ctDNA positive status (ctDNA+) after surgery is associated with a worse prognosis, and atezolizumab after surgery can provide benefit regardless of ctDNA status. Samples from 600 evaluable patients from IMpower010 were analyzed. 482 patients were ctDNA negative after surgery (post-op ctDNA-), and 118 patients were ctDNA+ after surgery (post-op ctDNA+). Atezolizumab was associated with increased disease free survival (DFS) in post-op ctDNA- patients, especially those with PD-L1 >=50% by SP263 (DFS HR 0.35), and a similar benefit was observed in post-op ctDNA+ patients (DFS HR 0.36). Among the post-op ctDNA + patients, 103 were evaluable for post-chemotherapy ctDNA and for longitudinal time-point analysis. ctDNA cleared in 62% of patients after chemotherapy (post-chemo ctDNA-), and ctDNA had not cleared in 38% of patients (post-chemo ctDNA+). Atezolizumab was associated with improved DFS compared to best supportive care (BSC), regardless of PD-L1 status and ctDNA clearance (HR 0.7 for post-chemo ctDNA- and HR 0.67 for post-chemo ctDNA+). Among post-chemo ctDNA- patients, atezolizumab was associated with a delay in conversion to ctDNA+ status (HR 0.6). Atezolizumab also stabilized post-chemo ctDNA levels in patients, compared to best supportive care. Although these post-hoc exploratory analyses are limited by small sample sizes, they provide further support for ctDNA as a prognostic biomarker and indicate that adjuvant atezolizumab therapy improves patient outcomes regardless of ctDNA status after surgery and after chemotherapy.
Long-term clinical benefits associated with durvalumab after chemoradiation for unresectable non-small cell lung cancer
58O. Real-world overall survival (OS) with durvalumab (D) after chemoradiotherapy (CRT) in patients (pts) with unresectable Stage III non-small-cell lung cancer (NSCLC): interim analysis from the PACIFIC-R study
Nicolas Girard (Institut Curie, Paris, France) reported results from the PACIFIC-R trial investigating the long-term effectiveness of consolidation therapy of durvalumab (D) after chemoradiotherapy (CRT) for stage III nonresectable non-small cell lung cancer (NSCLC). 1154 patients from ten countries participated in the study. At a median follow-up of 38.7 months, median overall survival (OS) had not yet been reached, but 60% of patients were estimated to be alive at three years. 24-month and 36-month OS rates were 72.35 and 63.2%, respectively. Median real world progression free survival (rwPFS) was 24.1 months. 24-month and 36-month rwPFS was 50.1% and 42.2%, respectively. Better clinical outcomes were observed in patients who received concurrent CRT, compared to sequential CRT and started durvalumab no more than 42 days after finishing radiotherapy. PD-L1 expression of invasive tumor cells (TC) was also associated with better clinical outcomes: 36-month OS for patients with PD-L1 positive tumors (TC >= 1%) was 67.0%, compared to 54.4% for patients with PD-L1 negative tumors (TC < 1%). Results from the PACIFIC-R trial are consistent with those of the PACIFIC trial and provide support for continued use of consolidation durvalumab therapy after CRT, especially in patients receiving concurrent CRT and in patients with PD-L1 positive tumors.
Comparing clinical efficacies of dostarlimab- to pembrolizumab-based treatment for first-line treatment of non-small cell lung cancer
57O. Randomized Double-Blind Phase II Trial (PERLA) of Dostarlimab + Chemotherapy (CT) vs Pembrolizumab + CT in Metastatic Non-Squamous NSCLC: Primary Results
Solange Peters (Lausanne University, Lausanne, Switzerland) presented primary results from PERLA, a global Phase II study comparing safety and efficacy of dostarlimab (D) with chemotherapy (CT) to pembrolizumab (P) with CT as first-line treatment for metastatic non-small cell lung cancer (NSCLC) without known driver mutations. This is the first large, global study to directly compare PD-1 inhibitors. D + CT (n=121) was associated with clinical benefits compared to P + CT (n=122), though these benefits were not significant. Overall response rates for D+CT and P+CT were 46% and 37%, respectively. Median progression free survival for D+CT and P+CT were 8.8 months and 6.7 months respectively. Overall response rates favored D+CT for PD-L1-high tumors (TPS > 50%), and P+CT was favored for PD-L1-negative tumors, though these differences were not significant. Similar trends were seen for PFS when patients were subdivided by PD-L1 status. In this direct comparison of PD-1 inhibitors, combining dostarlimab with chemotherapy exhibited similar ORR, DOR, and PFS compared to pembrolizumab with chemotherapy, and dostarlimab was favored over pembrolizumab in PD-L1 positive subgroups. These data support further investigation of incorporating dostarlimab with the current standard of care for first-line treatment of metastatic NSCLC.