BACKGROUND:The purpose of this study was to report an updated, final analysis with longer follow-up for the open-label phase III RATIONALE-304 study of first-line tislelizumab plus chemotherapy versus chemotherapy alone for advanced nonsquamous non-small-cell lung cancer (nsq-NSCLC). MATERIALS AND METHODS:Patients with histologically confirmed stage IIIB/IV nsq-NSCLC were randomized (2 : 1) to 4-6 cycles of tislelizumab plus platinum-based chemotherapy and pemetrexed every 3 weeks, followed by maintenance tislelizumab and pemetrexed, or platinum-based chemotherapy and pemetrexed alone every 3 weeks followed by maintenance pemetrexed. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFSIRC). Overall survival (OS), safety, and tolerability were secondary endpoints. RESULTS:Overall, 334 patients were randomized (tislelizumab plus chemotherapy: n = 223; chemotherapy: n = 111). At final analysis (median follow-up 16.1 months), safety/tolerability profiles in both arms were consistent with the interim analysis. Tislelizumab plus chemotherapy continued to demonstrate prolongation of PFSIRC versus chemotherapy alone {stratified hazard ratio (HR) 0.63 [95% confidence interval (CI) 0.47-0.86]; median PFSIRC 9.8 months (95% CI 8.9-11.7 months) versus 7.6 months (95% CI 5.6-8.0 months), respectively}. OS stratified HR for tislelizumab plus chemotherapy versus chemotherapy was 0.90 (95% CI 0.63-1.28), with median OS of 21.4 months (95% CI 17.7 months-not estimable) versus 21.3 months (95% CI 15.6 months-not estimable), respectively. At a subsequent ad hoc analysis (median follow-up 19.3 months), OS HR between arms was 0.85 (95% CI 0.63-1.14); when adjusted for crossover using the two-stage method, the OS HR was 0.68 (95% CI 0.48-0.96). CONCLUSIONS:After longer follow-up, first-line tislelizumab plus chemotherapy continued to demonstrate a manageable safety profile and a favorable PFS benefit over chemotherapy alone in patients with advanced/metastatic nsq-NSCLC.

INTRODUCTION:KRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. METHODS:Eligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. RESULTS:As of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7-58.6), and the disease control rate was 90.5% (95% CI: 83.7-95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6-11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). CONCLUSIONS:IBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

IBI351 is a covalent and irreversible inhibitor of KRASG12C. In a first-in-human phase I study (Zhou et al. Cancer Res 2023; 83: CT030), IBI351 showed promising efficacy in advanced NSCLC pts harboring KRASG12C. Here, we report results of IBI351 monotherapy for advanced NSCLC in an open-label, single-arm phase II pivotal study. Eligible NSCLC pts harboring KRASG12C who failed standard therapy were enrolled. IBI351 600 mg was orally administered twice daily. Primary endpoint was confirmed objective response rate (ORR) assessed by independent radiological review committee (IRRC) as per RECIST v1.1. Other endpoints were safety, IRRC confirmed disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS) and overall survival (OS). As of June 13, 2023, 116 pts were enrolled (median age: 63.0 years; males: 87.9%; ECOG PS 1: 91.4%; ≥2 prior lines of treatment: 41.4%; stage IV: 96.6%; brain metastasis: 30.2%). Median treatment duration was 188 days (range: 11-342) with 43 (37.1%) pts remaining on treatment. Unconfirmed ORR was 59.5% (95%CI: 50.0-68.5) and confirmed ORR was 46.6% (95%CI: 37.2-56.0) which reached pre-specified endpoint. DCR was 90.5% (95%CI: 83.7-95.2). Median DoR was 8.3 months (95%CI: 6.3-NC) with events occurring in 17 (31.5%) pts. 29 (53.7%) pts with confirmed response still on treatment. Median TTR was 1.4 months (range: 1.2-6.9). With a median follow-up of 8.2 months (95%CI: 7.0-8.3), median PFS was 8.3 months (95%CI: 5.6-10.4). Median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 105 (90.5%) pts while 47 (40.5%) pts had grade≥3 TRAEs. Common TRAEs were anemia (42.2%), alanine aminotransferase increased (27.6%), aspartate aminotransferase increased (27.6%), asthenia (26.7%) and protein urine present (25.0%). Serious TRAEs occurred in 26 (22.4%) pts. TRAEs leading to treatment discontinuation occurred in 8 (6.9%) pts. IBI351 continues to demonstrate encouraging efficacy with manageable safety. These results support IBI351 monotherapy as a potential new treatment option for advanced KRASG12C mutant NSCLC pts.

The phase Ⅲ CASPIAN study established durvalumab (D) plus etoposide with cisplatin or carboplatin (EP) as first-line standard of care (1L SoC) of ES-SCLC. The multicenter, single-arm, phase Ⅲb ORIENTAL study evaluated 1L D+EP in a large, real-world-like patient (pt) cohort in China. Preliminary safety and efficacy results were consistent with CASPIAN. Here we report final results and subgroup analysis.

Anlotinib plus EGFR-TKIs continuation was a potential treatment strategy in selected advanced non-small cell lung cancer (NSCLC) after disease progression in first-line EGFR-TKIs. This study aimed to evaluate the efficacy and safety of combined EGFR-TKIs and anlotinib. The trial aimed to enroll 120 patients after gradual or local progression in EGFR-TKIs treatment. All patients were treated with oral anlotinib 12 mg daily for 14 days every three weeks until disease progression or intolerable toxicity. The primary end-point was progression-free survival (PFS). The secondary end-points were 6 months and 12 months PFS rate, Overall response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. From July 08, 2019 to December 15, 2022 the enrollment was completed, including 109 patients with gradual progression. Up to December 31, 2022, 114 patients were available for efficacy assessment (105 patients had confirmed evaluation). Median PFS of combined anlotinib and EGFR-TKIs treatment was 9.2 months (95% CI, 6.6–11.6). Confirmed ORR was 5.7% and DCR was 92.4%. The PFS rate at 6 and 12 months was 66.3% and 36.7% respectively. Safety assessment was available in 116 patients, 94% (109/116) patients were reported treatment related adverse events (TRAEs). The incidence of grade 3 or 4 TRAEs was 36.2% (42/116) and the treatment-related serious adverse event (SAE) was 7.8% (9/116). The common TRAEs were diarrhea (47.4%), hypertension (42.2%), proteinuria (39.7%), and hypertrigly-ceridemia (24.1%). 22.4% (26/116) of patients experienced anlotinib dose reduction. EGFR-TKIs plus anlotinib demonstrated meaningful clinical control in advanced NSCLC after gradual or local progression in first-line EGFR-TKIs. And the toxicity was clinically manageable.

Chemotherapy-induced anemia (CIA) is a common complication of cancer and an important risk factor leading to poor prognosis for patients. Recombinant human erythropoietin-α (rHuEPO-α) is standard of care for CIA; however, safety concerns remain. Roxadustat is the first hypoxia-inducible factor prolyl hydroxylase inhibitor approved for treatment of anemia in chronic kidney disease. This study evaluated the efficacy and safety of roxadustat for anemia in patients with non-myeloid malignancies receiving multi-cycle treatments of myelosuppressive chemotherapy. In this open-label, non-inferiority, multicenter Phase III study conducted in China, patients were randomized (1:1) to receive oral roxadustat or subcutaneous rHuEPO-α three times weekly (TIW) for 12 weeks. Roxadustat starting dosage was 100 mg, 120 mg, and 150 mg TIW (patients weighing 40‒<50, 50–60, and >60 kg). rHuEPO-α starting dosage was 150 IU/kg TIW. Both roxadustat and rHuEPO-α dosages could be modified to achieve hemoglobin (Hb) concentrations of 100–120 g/L. Primary efficacy endpoint was least-squares mean (LSM) change in Hb concentration from baseline to the concentration averaged over Weeks 9‒13. Adverse events (AEs) were monitored. Of 159 patients randomized (n=82, roxadustat; n=77, rHuEPO-α), 140 were included in the per protocol set (n=78, roxadustat; n=62, rHuEPO-α). The LSM (95% 2-sided confidence interval [CI]) change from baseline to Weeks 9‒13 in Hb concentration was 17.1 (13.58, 20.71) g/L with roxadustat and 15.4 (11.34, 19.50) g/L with rHuEPO-α. The lower bound of the 1-sided 97.5% CI for the treatment difference (‒3.4 g/L) was greater than the predefined non-inferiority margin of ‒6.6 g/L, establishing non-inferiority. Results were supported by key secondary endpoints. AE rates were generally comparable between treatments and consistent with previous findings, supporting a positive benefit-risk profile. Oral roxadustat was non-inferior to subcutaneous rHuEPO-α for anemia in patients with non-myeloid malignancies receiving multi-cycle treatments of myelosuppressive chemotherapy.

NTRK gene fusions are oncogenic drivers of various solid tumour types. Entrectinib, a potent CNS-active TRK inhibitor, yielded systemic and intracranial responses in pts with NTRK-fp solid tumours in previous integrated analyses of three phase I/II trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). We present updated data with ∼30% more pts and longer follow-up (data cut-off: 2 Aug 2022). Adults with measurable, locally advanced/metastatic NTRK-fp solid tumours and ≥12 months’ follow-up from first on-study scan, who received ≥1 dose of entrectinib, were efficacy evaluable. The safety population comprised all pts who received ≥1 dose of entrectinib. Eligible pts from TAPISTRY (NCT04589845) were also included. Tumour responses were assessed by blinded independent central review per RECIST v1.1 at Week 4 and then every 8 weeks. Primary endpoints: objective response rate (ORR); duration of response (DoR). Key secondary endpoints: progression-free survival (PFS); overall survival (OS); safety. The efficacy-evaluable population comprised 194 pts with 17 types of solid tumours. Median age: 58 years (range 19–92); 63 (32.5%) pts received ≥2 prior lines of therapy. Median survival follow-up was 38.7 months. ORR was 62.4% (95% CI 55.2–69.2); the table shows responses in histologies with n>10. Median DoR was 29.4 months (95% CI 17.2–36.8). Median PFS and OS were 15.7 months (95% CI 13.7–22.9) and 38.2 months (95% CI 28.6–56.5), respectively. In the safety cohort (N=296), median treatment duration was 8.3 months (range 0.0–72.0). Of all pts with treatment-related adverse events (TRAEs; n=265), 57% had grade 1–2 TRAEs; dose reduction, interruption and discontinuation occurred in 24%, 34% and 6% of all pts, respectively.Table: 666PNTRK-fp tumour types* (n>10)Objective response rate, n/N (%)Total CNS metastases at baseline No CNS metastases at baseline121/194 (62.4) 22/36 (61.1) 99/158 (62.7)Non-small cell lung cancer32/51 (62.7)Sarcoma23/38 (60.5)Salivary (mammary analogue secretory carcinoma)27/31 (87.1)Thyroid14/21 (66.7)Breast8/13 (61.5)Colorectal cancer4/13 (30.8)*Other tumour types in the efficacy-evaluable cohort: neuroendocrine (n=7); head and neck (n=5); pancreatic (n=4); cancer of unknown primary (n=3); gynaecological (n=2); adrenal (n=1); cholangiocarcinoma (n=1); gastrointestinal (n=1); neuroblastoma (n=1); penile (n=1); prostate (n=1). Open table in a new tab *Other tumour types in the efficacy-evaluable cohort: neuroendocrine (n=7); head and neck (n=5); pancreatic (n=4); cancer of unknown primary (n=3); gynaecological (n=2); adrenal (n=1); cholangiocarcinoma (n=1); gastrointestinal (n=1); neuroblastoma (n=1); penile (n=1); prostate (n=1). In this updated analysis, entrectinib was well tolerated and continued to induce clinically meaningful responses in pts with NTRK-fp solid tumours.

Pucotenlimab is a novel anti-PD-1 IgG4 monoclonal antibody. Several clinical trials conducted in China have demonstrated its efficacy and safety in various solid tumors including gastric cancer and breast cancer. Here we report a phase II study result of pucotenlimab for nsq-NSCLC without EGFR/ALK mutations. In this open-label phase II study, patients naive to systemic treatment were enrolled with histologically diagnosed stage IIIB or IV nsq-NSCLC. Patients were received intravenous Pucotenlimab 200mg Q3w for up to 35 cycles, combined with platinum + pemetrexed Q3W for 4 cycles and followed by maintenance pemetrexed Q3W (all intravenous). The primary endpoint was overall response rate (ORR) and safety, and the secondary endpoints were progression-free survival (PFS), duration of response (DOR) and overall survival (OS). From September 25th, 2020 to April 15th, 2021, a total of 43 patients were enrolled and followed up with a median of 13.1 months by the cut-off date (August 3th, 2022). 22 patients achieved partial response and 20 remained stable disease, respectively, contributing an ORR of 48.8% (95%CI: 38.9%, 59.2%) and a DCR of 95.3% (95%CI: 88.7%, 98.4%). The median PFS, DOR were 11.1 months (95%CI: 6.8, 14.4) and 13.9 (95%CI: 6.6, NE) months, respectively. The median OS was not reached. The common treatment-related adverse events (TRAEs) of any grade included anemia (79.1%), neutrophil count decreased (72.1%), white blood cell count decreased (67.4%) and platelet count decrease (53.5%). Neutrophil count decreased (32.6%) was the most reported grade 3/4 TRAE. Pucotenlimab combined with pemetrexed plus platinum demonstrated promising efficacy and safety for the 1st line nsq-NSCLC patients without EGFR/ALK mutations.