Advanced Non-squamous Non-squamous Non-small Cell Lung Cancer Research Articles

Abstract CT282: MK-2870-004: A phase 3 study of MK-2870 (SKB264) versus chemotherapy for previously treated advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutations or other genomic alterations

Abstract Background: Trophoblast cell-surface antigen 2 (TROP2), a cell surface glycoprotein involved in the regulation of tumor growth and invasion, is broadly expressed and upregulated in several cancers, including NSCLC. MK-2870 (SKB264) is an antibody-drug conjugate (ADC) composed of the humanized anti-TROP2 monoclonal antibody, a hydrolytically cleavable linker, and the cytotoxic drug KL610023. MK-2870 has demonstrated encouraging antitumor activity and manageable toxicity in phase 1 and 2 studies of patients with solid tumors, including heavily pretreated EGFR-mutant NSCLC. We describe the design of the ongoing phase 3 MK-2870-004 study (NCT06074588) that will evaluate the efficacy and safety of MK-2870 vs chemotherapy for previously treated advanced or metastatic nonsquamous NSCLC with EGFR mutations or other genomic alterations. Trial design: The global, randomized, open-label, phase 3 MK-2870-004 study will enroll ~556 patients, including 456 with exon 19del or L858R EGFR mutations, and 100 with other genomic alterations. Eligible patients are aged ≥18 years with histologically or cytologically documented advanced (stage III not eligible for resection or curative radiation) or metastatic nonsquamous NSCLC with exon 19del or exon 21 L858R EGFR mutations or other genomic alterations in ALK, ROS1, BRAF V600E, NTRK, MET exon 14 skipping, or RET and those with less common EGFR mutations (exon 20 S768I, exon 21 L861Q, and/or exon 18 G719X). Patients must have progressive disease on or after 1 or 2 lines of prior tyrosine kinase inhibitor (TKI) therapy and a platinum-based therapy (may contain anti-PD-[L]1), measurable disease per RECIST v1.1, an available tumor sample, and adequate organ function. Prior EGFR TKI therapy must include a third-generation TKI for patients with T790M EGFR-mutant NSCLC. Patients with active central nervous system metastases or carcinomatous meningitis are ineligible, although those with previously treated and untreated stable brain metastasis are eligible for enrollment. Patients will be randomized (1:1) to MK-2870 4 mg/kg Q2W on Days 1, 15, and 29 of every 6-week cycle, or chemotherapy (docetaxel 75 mg/m2 Q3W or pemetrexed 500 mg/m2 Q3W) on Days 1 and 22 of every 6-week cycle. Randomization will be stratified by EGFR mutations with prior third generation TKI vs EGFR mutations with no prior third generation TKI vs other genomic alterations, brain metastasis (yes vs no), and TROP2 expression (low vs medium vs high). Dual primary endpoints are PFS (per RECIST v1.1 by blinded independent central review) and OS in patients with EGFR-mutant NSCLC. Key secondary endpoints include PFS and OS in all patients with NSCLC, ORR, DOR, patient-reported outcomes, and safety. Enrollment started in November 2023 and is currently ongoing. Citation Format: Federico Cappuzzo, Edward B. Garon, Myung-Ju Ahn, Shun Lu, Terufumi Kato, Enriqueta Felip, Parneet Cheema, Nicolas Girard, Mark Shamoun, Guoqing Wang, Bin Zhao, Rina Hui. MK-2870-004: A phase 3 study of MK-2870 (SKB264) versus chemotherapy for previously treated advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutations or other genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT282.

The cost-effectiveness of including liquid biopsy into molecular profiling strategies for newly diagnosed advanced non-squamous non-small cell lung cancer in an Asian population

ObjectivesLiquid biopsy is complementary to tissue biopsy for lung cancer profiling, yet evidence of the cost-effectiveness is limited. This could retard implementation and reimbursement in clinical practice. The aim of this study is to estimate the cost-effectiveness of profiling strategies that include liquid biopsy and to identify the optimal profiling approach for newly diagnosed advanced non-squamous non-small cell lung cancer (NSCLC) in an Asian population using Singapore as an example. Materials and methodsA decision tree and partitioned-survival model was developed from the Singapore healthcare system’s perspective to evaluate the cost-effectiveness of five molecular profiling strategies: either tissue or plasma next-generation sequencing (NGS) alone, a concurrent, and two sequential approaches. Model inputs were informed by local data or published literature. Sensitivity analyses and scenario analyses were undertaken to understand the robustness of the conclusions for decision making. The optimal strategy at different willingness-to-pay (WTP) thresholds was presented by cost-effectiveness acceptability frontier and the expected loss curve. ResultsThe sequential tissue-plasma NGS approach revealed an additional 0.0981 quality adjusted life years (QALYs) for an extra cost of S$3,074 over a 20-year time horizon compared to tissue NGS alone, resulting in an incremental cost-effectiveness ratio (ICER) of S$31,318/QALY and an incremental net monetary benefit of S$1,343 per patient. The findings were sensitive to the costs of pembrolizumab and osimertinib and the probabilities of re-biopsy after tissue NGS. Sequential plasma-tissue NGS and plasma NGS alone were more costly and less effective than alternatives. ConclusionThe sequential tissue-plasma NGS approach generated the highest net monetary benefit and was the optimal testing strategy when WTP was S$45,000/QALY. It retained superiority but understandably with a higher ICER when expensive, non-first line treatments were included. Overall, its routine clinical practice should be proactively considered for newly diagnosed advanced non-squamous NSCLC in an Asian population.

Real-world outcomes of Italian patients with advanced non-squamous lung cancer treated with first-line pembrolizumab plus platinum-pemetrexed

PurposeThe aim of this multi-center, retrospective/prospective cohort observational study was to evaluate outcomes in routine clinical practice of first-line chemo-immunotherapy with cis/carboplatin, pemetrexed and pembrolizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in 33 Italian centers. MethodsThe outcome measure was to evaluate overall survival (OS) in a real-world patient population. Secondary endpoints were: progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and incidence of treatment-related adverse events (AEs). Results1068 patients were enrolled at the time of data cut-off (January 31st, 2023), and 812 (76.0%) belonged to the retrospective cohort. Median age was 66 years (27−85), ECOG PS was ≥ 2 in 91 (8.6%) patients; 254 (23.8%) patients had brain metastases at baseline; 38 (3.6%) patients had tumor with PD-L1 expression ≥ 50%. After a median follow-up of 17.0 months (95% CI, 16.1–17.9), median OS was 16.1 months (95% CI, 14.4–18.8) and PFS was 9.9 months (95% CI, 8.8–11.2). Median DoR (n = 493) was 14.7 months (95% CI, 13.6–17.1). ORR was 43.4% (95% CI, 40.4–46.4). Any-grade AEs occurred in 636 (59.6%) patients and grade ≥ 3 in 253 (23.7%) patients. Most common grade ≥ 3 AEs were neutropenia (6.3%) and anemia (6.3%). ConclusionsFirst-line chemo-immunotherapy was effective and tolerable in this large, real-world Italian study of patients with advanced non-squamous NSCLC. Our results were in line with the KEYNOTE-189 registration study, also considering the low number of PD-L1 ≥ 50% patients included in our study.

First-generation EGFR-TKI plus bevacizumab and chemotherapy for advanced EGFR-mutated non-squamous non-small-cell lung cancer: a retrospective study

Background This study aimed to compare the efficacy and safety of different treatment modalities for previously untreated advanced EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC). Methods This retrospective study included 196 advanced EGFR-mutated non-squamous NSCLC. 107 received EGFR-tyrosine kinase inhibitor (EGFR-TKI) monotherapy (T), 53 received EGFR-TKI + bevacizumab (T + A), and 36 received EGFR-TKI + bevacizumab + chemotherapy (T + A + C). The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs). Results The median PFS was 27 months in the T + A + C group, 17 months in the T + A group, and 10 months in the T group. The multivariate analysis showed lower disease progression in the T + A + C group (HR, 0.377; 95% CI, 0.224–0.634; p < .001). Subgroup analysis showed that the T + A + C group did significantly improve PFS in patients with metastatic organs ≥2, brain metastases, liver metastases, and EGFR 19del compared to T + A group. No significant improvement in OS in the T + A + C group versus the T + A group, but a significant benefit in the subgroup of patients with metastatic organs ≥2. We also performed a subgroup analysis of the T + A + C group versus the T group, which similarly showed that the T + A + C group had better PFS than the T group in most subgroups, and the T + A + C group significantly improved OS in patients with metastatic organ ≥2 and liver metastases compared with the T group. The ORR was significantly higher in the T + A + C group than A + T and T groups (83.3% vs 71.7% vs 60.7%, p = .033). In safety, the T + A + C group had a higher incidence of AEs, but the majority was grade 1–2. The most frequent AEs of grade ≥ 3 were leukopenia (8.3%) and increased aminotransferase (8.3%) in the T + A + C group. Conclusions First-generation EGFR-TKI plus bevacizumab plus chemotherapy was a promising strategy for advanced EGFR-mutated non-squamous NSCLC.

Cemiplimab + Chemo Shows Clinical Benefit in Advanced NSCLC

Lung Cancer: Lung CancerFollow-up data from Part 2 of the Phase III EMPOWER-Lung 3 trial continues to demonstrate the clinical benefits of cemiplimab in combination with chemotherapy versus chemotherapy alone among patients with advanced squamous and non-squamous non-small cell lung cancer (NSCLC), across PD-L1 levels. These findings were presented during the 2023 European Lung Cancer Congress (Abstract 50) and published in the Journal of Thoracic Oncology (2023; doi: 10.1016/j.jtho.2023.03.008). “EMPOWER-Lung 3 (NCT03409614) is a double-blind, placebo-controlled, Phase III study evaluating first-line cemiplimab plus platinum-based chemotherapy versus chemotherapy alone for the treatment of patients with advanced NSCLC, irrespective of PD-L1 expression or histology,” noted lead study author Tamta Makharadze, MD, clinical oncologist at LTD High Technology Hospital Medical Center in Batumi, Georgia. The FDA approved cemiplimab plus platinum-based chemotherapy in November 2022 for the treatment of advanced non-small cell lung cancer in adults with EGFR, ALK, or ROS1 aberrations. This approval was supported by earlier data from the EMPOWER-Lung 3 trial. The primary analysis of the study, after 16.4 months of follow-up, demonstrated clinically meaningful and statistically significant improvements in overall survival, progression-free survival, objective response rate, and duration of response among patients treated with the combination versus chemotherapy alone, according to Makharadze, who presented the protocol specified final overall survival analysis during ELCC. Key Takeaways The study authors randomized patients 2:1 to receive 4 cycles of platinum-doublet chemotherapy combined with 350 mg cemiplimab (n=312) or placebo (n=154) every 3 weeks for up to 108 weeks. Eligible patients met the following criteria: treatment-naive advanced NSCLC (non-squamous and squamous histology; Stage IIIb/IV); any PD-L1 expression; no EGFR, ALK, or ROS1 aberrations; and ECOG performance status 0 or 1. Treated, clinically stable CNS metastases were also allowed. Overall survival was the primary endpoint. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). After a median follow-up of 28.4 months, Makharadze and colleagues found that cemiplimab in combination with chemotherapy continued to demonstrate significantly improved overall and PFS compared with chemotherapy alone. Data showed a median overall survival of 21.1 months among patients treated with cemiplimab plus chemotherapy compared with 12.9 months for individuals who received chemotherapy alone. Cemiplimab plus chemotherapy also led to improved progression-free survival versus chemotherapy alone at 8.2 months and 5.5 months, respectively. Makharadze reported an objective response rate of 43.6 percent for the combination arm and 22.1 percent for the chemotherapy-only group. Duration of response was 16.4 and 7.3 months, respectively. An exploratory analysis supported the clinical benefit of cemiplimab in combination with chemotherapy in both squamous and non-squamous histologies. Among patients with squamous disease, Makharadze noted that the median overall survival with cemiplimab plus chemotherapy was 22.3 months versus 13.8 months with chemotherapy alone. The median PFS in this group was 8.2 months and 4.9 months, respectively. Among patients with non-squamous disease, the median overall survival for the cemiplimab combination and chemotherapy-only arms was 19.4 months and 12.4 months, respectively. The study authors observed a median PRS of 7.9 months for patients treated with cemiplimab plus chemotherapy compared with 5.7 months in those who only received chemotherapy. The study authors also performed an exploratory analysis examining efficacy according to PD-L1 expression level, and Makharadze noted during her presentation that “all data favored the cemiplimab plus chemotherapy arm except the overall survival data for patients with less than 1 percent PD-L1 expression. “However, when we are seeing the PFS and ORR data, which are a more proximal and prominent measure of drug efficacy, all data favor cemiplimab plus chemotherapy—even data for patients with a less than 1 percent PD-L1 expression level,” she said. Study authors found that the safety profiles for longer-term use of cemiplimab in combination with chemotherapy were generally consistent with previously reported data. Grade ≥3 treatment-emergent adverse events occurred in 48.7 percent of patients who received cemiplimab plus chemotherapy and among 32.7 percent of individuals who were given chemotherapy alone. This trial was also supported by patient-reported outcomes, according to Makharadze, who noted that “pain was clinically decreased in the group [treated with] cemiplimab plus chemotherapy. These data indicated that cemiplimab plus chemotherapy did not impose toxicity that significantly interfered with quality of life of patients with non-small cell lung cancer.” At 28.4 months, the EMPOWER-3 Lung trial continues to demonstrate an improvement in the benefits associated with cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous and non-squamous NSCLC, regardless of PD-L1 expression level and without EGFR, ALK, or ROS1 aberrations, the study authors stated. Summarizing their findings, Makharadze noted, “Longer-term follow-up of patients with advanced non-small cell lung cancer demonstrated that first-line cemiplimab plus chemotherapy continued to show clinically meaningful and statistically significant improvement versus chemotherapy alone. “Cemiplimab plus chemotherapy also continued to show an acceptable safety profile compared to chemotherapy alone. This finding is supported by favorable patient-reported outcomes and the safety profile is generally consistent with primary analysis,” she noted. “This data support the use of cemiplimab plus chemotherapy as first-line treatment for patients with advanced non-small cell lung cancer across histologies and PD-L1 expression rate.” Catlin Nalley is a contributing writer.

Phase 1b/2 study of surufatinib in combination with docetaxel as second-line treatment of advanced driver-gene negative non-squamous non-small cell lung cancer (NSCLC).

e21087 Background: Advanced driver-gene negative non-squamous NSCLC has few second-line treatment choices. Surufatinib is a new antiangiogenic drug that potently inhibits VEGFR1，2，3, FGFR1 and CSF-1R. The purpose of this trial was to determine the recommended phase 2 dose of surufatinib in combination with docetaxel through a phase 1b study and to further analyze the preliminary efficacy and safety of the combination therapy in patients with advanced driver-gene negative non-squamous NSCLC. Methods: Advanced driver-gene negative non-squamous NSCLC patients progressed after first-line platinum-based chemotherapy (the combination with immune checkpoint inhibitors and/or bevacizumab was allowed) were enrolled to treat with surufatinib in combination with docetaxel. Using a 3 + 3 study design in the phase 1b dose-escalation portion, patients received surufatinib at doses ranging from 200 mg/day to 300 mg/day for 21 days per cycle. Surufatinib was started at a dose of 250 mg/day and exploratory dose of 300 mg/day if no patients develop dose-limiting toxicity (DLT) in the first 3 patients in the first treatment cycle. If 2 or more of the 3 patients develop DLT, exploratory dose of 200 mg/day. Concomitant treatment with docetaxel at a dose of 60 mg/m2. The primary objective of the study was the recommended phase 2 dose of surufatinib in combination with docetaxel. The secondary objective was the preliminary efficacy and safety. Results: At data cut-off (December 31, 2022), we recruited 9 patients in phase 1b portion. Three patients were enrolled in the surufatinib 250 mg/day dose cohort. Among them, 2 developed DLT (1 patient with grade 3 oral mucositis and 1 patient with grade 3 elevated blood bilirubin) which did not recur with a reduction of dosage to 200 mg/day. A total of 6 patients were enrolled in the 200 mg/day dose cohort and 1 patient developed DLT (grade 3 diarrhoea). The recommended phase 2 dose was established as surufatinib 200 mg/day combined with docetaxel 60 mg/m2.At present, there were 3 patients enrolled in phase 2. Among the 12 patients enrolled in this study, 1 patient was lost and 11 patients were assessable for treatment efficacy and safty. The objective response rate (ORR) was 27.2% (3/11) and the disease control rate (DCR) was 100%. The median progression free survival (PFS) was 5.8 months (95% CI = 2.1-9.4). The most common treatment-related adverse events (AEs) were diarrhoea (33.3%), neutropenia (41.7%), hypertension (25%), and anaemia (33.3%). Common grade 3 AEs included diarrhoea (16.7%), neutropenia (33.3%) and anaemia (16.7%), with no unexpected treatment-related AEs (TRAEs). Conclusions: Surufatinib in combination with docetaxel was an effective second-line treatment for patients with advanced driver-gene negative non-squamous NSCLC. The clinical benefit was encouraging, and the safety profile was acceptable. Clinical trial information: ChiCTR2100047313 .

Phase 1b/2a safety and tolerability study of bemcentinib (BEM) with pembrolizumab/carboplatin/pemetrexed in first line (1L) advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) without/with a STK11 mutation.

TPS9154 Background: The combination of platinum, pemetrexed, and pembrolizumab (CIT) has become the standard of care in 1L non–oncogene addicted NSCLC. Despite an initial improvement in response rate and survival, the 5-year survival of NSCLC remains approximately 20-30%, due to the emergence of primary and acquired resistance. Additionally, the presence of brain metastases occurs in ˜30-50% of NSCLC patients and confers a poor prognosis. Among the currently non-actionable mutations, STK11/LKB1 mutations (STK11m) are common (˜20%) in NSCLC. Recent evidence suggests that STK11m NSCLC patients have a minimal response to checkpoint inhibitors and to chemo-immunotherapy in the first line setting. STK11m tumors are characterized by an immune-suppressed phenotype which is highly associated with AXL signalling. BEM, a first-in-class, oral, selective AXL inhibitor, has demonstrated the ability to prevent chemoresistance, re-sensitize STK11m NSCLC tumors to pembrolizumab, and enhance efficacy of CIT in preclinical lung models. Moreover, following oral administration, BEM readily distributes in brain tumour tissue in recurrent glioblastoma patients, with a 25.9 mean ratio of drug concentration in brain tissue to plasma. Therefore, the addition of BEM to CIT has the potential to improve 1L treatment outcomes in NSCLC overall and particularly in STK11m tumors. Methods: This is an open-label, multi-center, phase 1b/2a study to assess the safety, tolerability, and preliminary anti-tumor activity of BEM + CIT as 1L treatment in patients with advanced (Stage IIIb/IIIc) or metastatic (Stage IV) non-squamous NSCLC without actionable mutations. Patients with stable brain metastases are eligible to participate. Phase 1b follows a 3+3 design and will explore CIT in combination with one of 3 BEM dose levels: Cohort 1 = 75mg; Cohort 2 = 100 mg; or Cohort 3 = 150 mg. BEM is administered orally once/day on Day 1 of each 21-day treatment cycle. After 4 cycles of CIT + BEM, maintenance with BEM + pemetrexed + pembrolizumab is administered for up to 2 years. An independent data safety monitoring board will assess the safety data at the end of the dose-limiting toxicity period (the first 21 days of treatment for each patient, i.e. cycle 1) of each cohort and will recommend the BEM dose for the phase 2a expansion. In the phase 2a, up to 40 patients harboring a STK11m (regardless of their co-mutational status), in the absence of driver mutations will be enrolled. The study will include extensive co-mutational analyses via next-generation sequencing to identify potential sub-groups of patients deriving particular benefit. The trial is open to patient enrolment in phase1b in the US; recruitment for phase 2a is planned to open in Q2 2023 in Europe and US. EudraCT 2019‐003806‐28/NA/124645. Clinical trial information: NCT05469178 .

Immunotherapy or antiangiogenic therapy plus chemotherapy as first-line treatment of patients with PD-L1(-) advanced non-squamous non-small cell lung cancer in a Chinese cohort.

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 first-line regimens for patients with advanced nonsquamous NSCLC who were negative for PD-L1. 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. 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. Bevacizumab plus chemotherapy outperformed immunotherapy plus chemotherapy in terms of PFS.

Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial

In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results. This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing). Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group. This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up. National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

A cost-effectiveness analysis of first-line toripalimab plus chemotherapy in advanced nonsquamous non-small cell lung cancer in China

ABSTRACT Background This study compares first-line toripalimab with chemotherapy for advanced nonsquamous non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Research design and methods A three-state Markov model was established to compare the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) of first-line toripalimab plus chemotherapy versus chemotherapy. Clinical outcomes data were acquired from the CHOICE-01 clinical trials. Costs and utilities were gathered from regional databases or published publications. One-way sensitivity and probability sensitivity analyses were used to investigate the stability of the model parameters. Results First-line toripalimab treatment for advanced nonsquamous NSCLC resulted in an incremental cost of $16,214.03 and added 0.77 QALYs compared to chemotherapy, which had an ICER of $21,057.18 per QALY gained. The ICER was substantially lower than the willingness to pay (WTP) threshold in China, which was $37,663.26 per QALY. The toripalimab cycle used was shown to have the greatest impact on the ICERs, according to sensitivity analysis, although none of the factors significantly affected the model’s outcomes Conclusions Toripalimab plus chemotherapy is likely to be a cost-effective option compared with chemotherapy alone for patients with advanced nonsquamous NSCLC from the perspective of the Chinese healthcare system.

Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study

BackgroundThis multicenter phase 2 trial evaluated the safety and efficacy of osimertinib and platinum-based chemotherapy (OPP) in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer (NSCLC). Patients and methodsPatients received osimertinib 80 mg once daily (QD), with either cisplatin 75 mg/m2 (arm A) or carboplatin (area under the curve [AUC] = 5; arm B), plus pemetrexed 500 mg/m2 for four cycles and maintenance therapy of osimertinib 80 mg QD with pemetrexed 500 mg/m2 every 3 weeks. The primary end-points were safety and objective response rate (ORR), and the secondary end-points were complete response rate (CRR), disease control rate (DCR), and progression-free survival (PFS). ResultsIn total, 67 patients (34 in arm A and 33 in arm B) were enrolled between July 2019 and February 2020. At the data cutoff (28th February 2022), 35 (52.2%) patients had discontinued the protocol treatment, including 10 (14.9%) due to adverse events. No treatment-related deaths occurred. In the full analysis set, the ORR, CRR, and DCR were 90.9% (95% confidence interval [CI], 84.0–97.8), 3.0% (0.0–7.2), and 97.0% (92.8–100.0), respectively. Based on updated survival data (data cutoff on August 31, 2022, median follow-up time: 33.4 months), the median PFS was 31.0 months (95% CI, 26.8 months–not reached) and median overall survival was not reached. ConclusionsThis is the first study to show that OPP has excellent efficacy with acceptable toxicity in previously untreated EGFR-mutated advanced non-squamous NSCLC patients.

Development and validation of a decision model for the evaluation of novel lung cancer treatments in the Netherlands

Recent discoveries in molecular diagnostics and drug treatments have improved the treatment of patients with advanced (inoperable) non-squamous non-small cell lung cancer (NSCLC) from solely platinum-based chemotherapy to more personalized treatment, including targeted therapies and immunotherapies. However, these improvements come at considerable costs, highlighting the need to assess their cost-effectiveness in order to optimize lung cancer care. Traditionally, cost-effectiveness models for the evaluation of new lung cancer treatments were based on the findings of the randomized control trials (RCTs). However, the strict RCT inclusion criteria make RCT patients not representative of patients in the real-world. Patients in RCTs have a better prognosis than patients in a real-world setting. Therefore, in this study, we developed and validated a diagnosis-treatment decision model for patients with advanced (inoperable) non-squamous NSCLC based on real-world data in the Netherlands. The model is a patient-level microsimulation model implemented as discrete event simulation with five health events. Patients are simulated from diagnosis to death, including at most three treatment lines. The base-model (non-personalized strategy) was populated using real-world data of patients treated with platinum-based chemotherapy between 2008 and 2014 in one of six Dutch teaching hospitals. To simulate personalized care, molecular tumor characteristics were incorporated in the model based on the literature. The impact of novel targeted treatments and immunotherapies was included based on published RCTs. To validate the model, we compared survival under a personalized treatment strategy with observed real-world survival. This model can be used for health-care evaluation of personalized treatment for patients with advanced (inoperable) NSCLC in the Netherlands.

Tislelizumab plus chemotherapy is more cost-effective than chemotherapy alone as first-line therapy for advanced non-squamous non-small cell lung cancer.

Tislelizumab is a programmed cell death protein-1 (PD-1) inhibitor. Tislelizumab plus chemotherapy as first-line option for advanced non-squamous non-small cell lung cancer (NSCLC), compared with chemotherapy alone, resulted in significantly prolonged survival outcomes; however, evidence regarding its relative efficacy and cost is lacking. We aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy compared with that of chemotherapy alone, from the health care perspective in China. A partitioned survival model (PSM) was used for this study. The survival data were obtained from the RATIONALE 304 trial. Cost-effectiveness was defined as incremental cost-effectiveness ratio (ICER) less than the willingness to pay (WTP) threshold. Incremental net health benefits (INHB), incremental net monetary benefits (INMB), and subgroup analyses were also assessed. Sensitivity analyses were further established to assess the model stability. Compared with chemotherapy alone, tislelizumab plus chemotherapy increased by 0.64 quality-adjusted life-years (QALYs) and 1.48 life-years, and yielded an increase of $16,631 in cost per patient. The INMB and INHB were $7,510 and 0.20 QALYs at a WTP threshold of $38,017/QALY, respectively. The ICER was $26,162/QALY. The outcomes were most sensitive to the HR of OS for tislelizumab plus chemotherapy arm. The probability of tislelizumab plus chemotherapy being considered cost-effective was 87.66% and >50% in most of the subgroups at the WTP threshold of $38,017/QALY. At the WTP threshold of $86,376/QALY, the probability achieved 99.81%. Furthermore, the probability of tislelizumab plus chemotherapy being considered cost-effective in subgroups of patients with liver metastases and PD-L1 expression ≥50% were 90.61 and 94.35%, respectively. Tislelizumab plus chemotherapy is likely to be cost-effective as a first-line treatment for advanced non-squamous NSCLC in China.

Cost-effectiveness analysis of atezolizumab plus chemotherapy as first-line treatment for patients with advanced nonsquamous non-small-cell lung cancer in China

ABSTRACT Objective The aim of the study was to evaluate the cost-effectiveness of adding atezolizumab to first-line chemotherapy for advanced nonsquamous non-small-cell lung cancer (NSCLC) from Chinese healthcare system. Methods A partitioned survival model (PSM) was established to simulate 3-week patients transition in a 20-year time horizon to estimate the health and economic outcomes of adding atezolizumab to first-line chemotherapy for advanced nonsquamous NSCLC. Costs and utility values were obtained from the local charges and published studies. Sensitivity analyses were conducted to confirm the robustness of the model results. Results Atezolizumab plus chemotherapy yielded additional 0.36 life years (LYs) and 0.23 quality-adjusted life-years (QALYs), and the marginal cost was $60,154.48, resulting in an ICER of atezolizumab plus chemotherapy versus chemotherapy was $267,264.85/QALY. One-way sensitivity analyses revealed that the cost of atezolizumab was the main driver of the model outcomes, and the probabilistic sensitivity analyses suggested that atezolizumab plus chemotherapy had 0% probability of being cost-effective first-line option at the willingness-to-pay (WTP) threshold of $37,652/QALY in China. Conclusions Atezolizumab plus chemotherapy could not be considered cost-effective compared with chemotherapy alone as the first-line strategy for patients with advanced nonsquamous NSCLC in China. And appropriately reduce the price of atezolizumab is necessary.

Cost-effectiveness analysis of sintilimab plus pemetrexed and platinum versus chemotherapy alone as first-line treatment in metastatic non-squamous non–small cell lung cancer in China

ObjectiveIn frst-line treatment of advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC), the ORIENT-11 study demonstrated a signifcant progression-free survival and overall survival for sintilimab plus chemotherapy in comparison with chemotherapy alone. But the cost-effectiveness of the two treatment schemes is unclear in China. The objective of the current study was to evaluate the cost efectiveness of sintilimab plus chemotherapy versus Platinum-based chemotherapy for locally advanced or metastatic squamous NSCLC in China.MethodsWe performed an economic evaluation from the perspective of the Chinese healthcare system using a partitioned survival model with three mutually exclusive health states: progression free, post-progression, and death. The circulation cycle of the model was 3 weeks and the study time limit was 10 years. Efficacy data were obtained from the ORIENT-11 clinical trial. Cost and utility values were derived from published studies and online price databases. The primary outcomes of the model were quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). One-way sensitivity analysis and probability sensitivity analysis were used to verify the robustness of the base-case analysis results.ResultsSintilimab plus chemotherapy provided an additional 0.6 QALYs. The total cost per patient was CNY¥413,273.16 for sintilimab plus chemotherapy and CNY¥280,695.23 for Platinum-based chemotherapy. The ICER for sintilimab plus chemotherapy was CNY¥220,963.22/QALY. Sensitivity analyses found the results to be most sensitive to the cost of pemetrexed and utilities of PF state. In the probabilistic sensitivity analysis, sintilimab was cost-efective in 78.6% of the simulations, assuming a willingness-to-pay threshold (WTP) of CNY¥242,928 per QALY.ConclusionCompared with chemotherapy alone, the sintilimab plus chemotherapy is likely to be a cost-effective option as the first-line treatment for locally advanced or metastatic nonsquamous NSCLC in China.

Effect of EGFR amplification on the prognosis of EGFR-mutated advanced non–small-cell lung cancer patients: a prospective observational study

BackgroundEpidermal growth factor receptor (EGFR) amplification refers to the copy number increase of EGFR gene, and is often identified as a “bypass” way of Epidermal growth factor receptor Tyrosine kinase inhibitors (EGFR-TKI) resistance. We aimed to explore the effect of EGFR amplification on EGFR mutation treatment-naive advanced non-squamous non-small cell lung cancer (NSCLC) patients.MethodsWe conducted a prospective observational study in single center, enrolling advanced non-squamous NSCLC patients receiving Tyrosine kinase inhibitors (TKIs) between March 3, 2019, and February 1, 2022. Next-generation sequencing (NGS) was used to detect genetic alterations in tumor tissue samples. Progression-free survival (PFS) curves were performed using the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate factors affecting the efficacy of TKIs.ResultsA total of 117 treatment-naive advanced NSCLC patients were identified in this study. EGFR amplification was found in 22 of 117 (18.8%) patients with EGFR mutations. Of 22 patients with EGFR amplification, 10 patients harbored EGFR 19 del, 11 patients with 21-L858R. The median follow-up time was 22.47 months. The median PFS of the patients with or without EGFR amplification was 8.25 months and 10.67 months, respectively (log-rank test, P = 0.63). In multivariate analysis, EGFR amplification was not an independent prognosis factor for the patients receiving first-line TKIs [HR = 1.38, 95%CI (0.73–2.58), P = 0.321]. Subgroup analysis revealed that EGFR amplification is a risk factor for progression in the brain metastasis population. [HR = 2.28, 95%CI (1.01, 5.14), P = 0.047].ConclusionEGFR amplification is not an independent prognosis factor for PFS in advanced non-squamous NSCLC patients receiving first-line TKIs. However, it is an independent risk factor for PFS in the brain metastasis population.

Up-front mutation detection in circulating tumor DNA by droplet digital PCR has added diagnostic value in lung cancer

Identification of actionable mutations in advanced stage non-squamous non-small-cell lung cancer (NSCLC) patients is recommended by guidelines as it enables treatment with targeted therapies. In current practice, mutations are identified by next-generation sequencing of tumor DNA (tDNA-NGS), which requires tissue biopsies of sufficient quality. Alternatively, circulating tumor DNA (ctDNA) could be used for mutation analysis. This prospective, multicenter study establishes the diagnostic value of ctDNA analysis by droplet digital PCR (ctDNA-ddPCR) in patients with primary lung cancer.CtDNA from 458 primary lung cancer patients was analyzed using a panel of multiplex ddPCRs for EGFR (Ex19Del, G719S, L858R, L861Q and S768I), KRAS G12/G13 and BRAF V600 mutations. For 142 of 175 advanced stage non-squamous NSCLC patients tDNA-NGS results were available to compare to ctDNA-ddPCR. tDNA-NGS identified 98 mutations, of which ctDNA-ddPCR found 53 mutations (54%), including 32 of 45 (71%) targetable driver mutations. In 2 of these 142 patients, a mutation was found by ctDNA-ddPCR only. In 33 advanced stage patients lacking tDNA-NGS results, ctDNA-ddPCR detected 15 additional mutations, of which 7 targetable.Overall, ctDNA-ddPCR detected 70 mutations and tDNA-NGS 98 mutations in 175 advanced NSCLC patients. Using an up-front ctDNA-ddPCR strategy, followed by tDNA-NGS only if ctDNA-ddPCR analysis is negative, increases the number of mutations found from 98 to 115 (17%). At the same time, up-front ctDNA-ddPCR reduces tDNA-NGS analyses by 40%, decreasing the need to perform (additional) biopsies.

Patterns of renal toxicity from the combination of pemetrexed and pembrolizumab for advanced nonsquamous non-small-cell lung cancer (NSCLC): A single-center experience

ObjectivesThe combination of immune-checkpoint inhibitors (ICI) and platinum-pemetrexed chemotherapy (CT) in first-line setting improved survival outcomes of advanced non-small cell lung cancer (NSCLC) patients. Among the various adverse events, renal toxicity can be a relevant safety issue. Materials and methodsWe conducted a single-center, observational retrospective study including consecutive patients treated with upfront CT-ICI for advanced nonsquamous NSCLC to investigate incidence and clinical characteristics of acute kidney injury (AKI) using ‘Acute Kidney Injury Working Group of Kidney Disease: Improving Global Outcomes’ (KDIGO) definition. ResultsA total of 89 patients received a first-line CT/ICI. The median age was 69 years. 60.7 % were male, and 87.6 % had an ECOG PS of 0–1. 92.1 % had a baseline glomerular filtration rate of at least 60 ml/min. According to KDIGO criteria, 25 (28 %) patients developed AKI. Considering risk factors for AKI onset, patients receiving >10 cycles of CT/ICI were more likely to experience AKI (p < 0.001). No other associations were found with other variables, including concomitant medications. Any component of the treatment was discontinued (pemetrexed pembrolizumab or both) in 10 (40 %) patients, and 9 patients (36 %) were addressed to nephrological consultation. These patients had higher mean creatinine variation from baseline (1 vs 0.6 mg/dl, p = 0.025) and creatine level (1.8 vs 1.4 mg/dl, p = 0.015), but lower eGFR (35.7 vs 54.2 ml/min, p = 0.011) in comparison to patients not addressed. No patients had microscopic hematuria or pyuria, but mild proteinuria (<0.8 g/24 h) was found in 4 patients. A renal biopsy was performed on 3 patients, revealing acute tubule interstitial nephritis (ATIN), karyomegalic interstitial nephritis, and acute tubular necrosis (ATN). ConclusionRenal toxicity represents a challenging adverse event that could negatively impact outcomes of metastatic nonsquamous NSCLC patients receiving CT/ICI demanding a multidisciplinary approach.

Association of thyroid transcription factor-1 (TTF-1) expression with efficacy of PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in advanced non-squamous non-small cell lung cancer.

Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died [median follow-up 14.6 months (range, 0.53-29.5 months)]. PFS was longer for TTF-1-positive patients than for TTF-1-negative patients [median, 12.2 vs. 6.0 months; hazard ratio (HR) =0.63 (95% CI: 0.37-1.06); log-rank P=0.028]. IPTW-adjusted PFS was significantly longer for TTF-1-positive than for TTF-1-negative patients [HR =0.62 (95% CI: 0.46-0.83); log-rank P=0.024]. TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

Immunotherapy combined with chemotherapy versus chemotherapy alone as the first-line treatment of PD-L1-negative and driver-gene-negative advanced nonsquamous non-small-cell lung cancer: An updated systematic review and meta-analysis.

This meta-analysis aimed to compare the efficacy of immunotherapy combined with chemotherapy versus chemotherapy alone as the first-line therapy for patients with programmed death ligand-1 (PD-L1)-negative and driver-gene-negative advanced nonsquamous non-small-cell lung cancer (NSCLC). Eligible randomized trials were identified following the systematic search of PubMed, Cochrane Library, Embase, Web of Science, Wanfang Data, and China Knowledge Resource Integrated Database from January 2000 to June 2022. Seven trials involving 1132 patients with PD-L1-negative and driver-gene-negative advanced nonsquamous NSCLC were included. Immunotherapy combined with chemotherapy showed significantly superior objective response rate (ORR) compared with chemotherapy alone (odds ratio 2.81, 95% confidence interval [CI] 1.69-4.65). Immunotherapy combined with chemotherapy also significantly prolonged the progression-free survival (PFS) (hazard ratio [HR] 0.63, 95% CI 0.55-0.74, p < 0.001) and overall survival (OS) (HR 0.68, 95% CI 0.56-0.82, p < 0.001) of patients with PD-L1-negative and driver-gene-negative advanced nonsquamous NSCLC compared to chemotherapy alone. In terms of ≥3 treatment-related adverse events, patients receiving immunotherapy combined with chemotherapy were at higher risk than chemotherapy alone (OR 1.73, 95% CI 1.47-2.05). This meta-analysis suggested that immunotherapy combined with chemotherapy yielded a better ORR, PFS, and OS, and a higher incidence of treatment-related adverse events as the first-line therapy for patients with PD-L1-negative and driver-gene-negative nonsquamous advanced NSCLC in comparison to chemotherapy alone. A rational treatment protocol should be selected according to the individual condition of the patients.