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

Efficacy and safety of immune checkpoint inhibitors in post-TKI NSCLC patients harboring EGFR mutations.

Immune checkpoint inhibitors (ICIs) have been validated in epidermal growth factor receptor (EGFR) wild-type advanced non-small cell lung cancer (NSCLC) patients. However, there exists no evidence regarding NSCLC patients harboring EGFR mutations, experiencing EGFR-TKI (tyrosine kinase inhibitor) treatment failure. We collected clinical information from real world and conducted a time series-based meta-analysis to determine the efficacy and safety of ICIs in patients harboring EGFR mutations and experienced EGFR-TKIs resistance. Twenty-two NSCLC patients with EGFR mutations after TKI resistance were included from two hospitals. PubMed, Embase and Cochrane Library were searched for relevant literature published until December 31, 2021. Endpoint outcomes included mortality and progression-free survival (PFS) at different times of follow-up. In total, 22 patients showed that the median PFS was 5.6months (range 2.0-9.0months). According to treatment strategies, the median PFS was 2.4months (range 2.0-5.3months) in the ICI monotherapy group and 5.9months (range 2.8-9.0months) in the ICI combined Chemotherapy group. Additionally, sixteen studies, including 5 trials, 10 controlled cohorts and 1 real-world study, were assessed, involving a total of ICI-treated NSCLC patients with EGFR mutation after TKI failure. The 6-month survival and PFS rate were 0.82 (95% CI 0.36-0.97) and 0.55 (95% CI 0.34-0.74), respectively. ICI combined chemotherapy showed the best survival outcome among these groups, as demonstrated by the 12-month survival rate and PFS. No new safety signals were identified with the combination therapy. The frequency of treatment-related adverse events was similar to that in previously reported studies of chemotherapy combined with checkpoint inhibitors. The addition of ICIs plus chemotherapy may significantly improve progression-free survival among patients with locally advanced or metastatic non-squamous NSCLC who EGFR-TKIs resistance.

Abstract CT552: RATIONALE 304: Tislelizumab (TIS) plus chemotherapy versus chemotherapy alone as first-line (1L) treatment for non-squamous (non-sq) NSCLC in patients (pts) aged 65-75 years

Abstract Background: Primary results from the Phase 3 RATIONALE-304 study (NCT03663205) showed efficacy and a manageable safety/tolerability profile for TIS, an anti-programmed cell protein 1 monoclonal antibody, plus chemotherapy, as 1L treatment for non-sq NSCLC. We report results from pts aged 65-75 years. Methods: In RATIONALE-304, eligible pts (18-75 years) were treatment-naïve and had locally advanced or metastatic non-sq NSCLC. Pts were stratified by disease stage and programmed death-ligand 1 expression, and randomized 2:1 to receive TIS (200 mg intravenously [IV]) plus platinum (carboplatin AUC 5 or cisplatin 75 mg/m2 IV) plus pemetrexed 500 mg/m2 every three weeks for 4-6 cycles followed by maintenance TIS plus pemetrexed (Arm A), or platinum pemetrexed for 4-6 cycles followed by maintenance pemetrexed (Arm B). Progression-free survival (PFS) by independent review committee (IRC), objective response rate (ORR), and safety were assessed in pts aged 65-75 years. Results: In total, 97 pts aged 65-75 years were randomized to Arm A (60 pts) or Arm B (37 pts). The median age of pts was 68.0 years, and 76 pts (78.4%) were male. PFS was longer, and ORR higher, in Arm A vs Arm B (Table). Overall, 59 pts in Arm A, and 37 pts in Arm B experienced ≥ 1 treatment-emergent adverse event (TEAE). In Arm A, Grade ≥ 3 TEAEs occurred in 43 (72.9%) pts aged 65-75 years vs 150 (67.6%) aged ≥ 18 years, and in Arm B, 18 (48.6%) pts aged 65-75 years vs 59 (53.6%) pts aged ≥ 18 years. TEAEs leading to permanent discontinuation of any component of study treatment occurred in 19 (32.2%) pts in Arm A, and 5 (13.5%) pts in Arm B. 21 (35.6%) pts receiving TIS experienced ≥ 1 immune-related TEAE. Conclusions: Observed improvements in PFS and ORR support the treatment benefits of TIS in combination with platinum and pemetrexed chemotherapy in pts aged 65-75 with advanced non-squamous NSCLC. The safety profile of TIS in pts aged 65-75 years was similar to the safety profile for all pts in the overall study population. Table Arm A (N=60) Arm B (N=37) PFS Events (%) 27 (45.0) 20 (54.1) HR (95% CI) 0.727 (0.407, 1.297) - Median, months (95% CI) 9.7 (5.75, 11.53) 7.7 (4.21, 9.76) ORR, % (95% CI) 53.3 (40.0, 66.3) 40.5 (24.8, 57.9) HR, hazard ratio Citation Format: Shun Lu, Jie Wang, Yan Yu, Xinmin Yu, Yanping Hu, Zhiyong Ma, Xingya Li, Wu Zhuang, Yunpeng Liu, Weidong Li, Jiuwei Cui, Dong Wang, Wangjun Liao, Mengzhao Wang, Jianying Zhou, Zhehai Wang, Yuping Sun, Wanyu He, Yuanyuan Bao. RATIONALE 304: Tislelizumab (TIS) plus chemotherapy versus chemotherapy alone as first-line (1L) treatment for non-squamous (non-sq) NSCLC in patients (pts) aged 65-75 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT552.

Abstract 5539: Nivolumab after cyclophosphamide and doxorubicin induction therapy in previously treated advanced non-squamousl non-small cell lung cancer with PD-L1<10%

Abstract Purpose: Immune checkpoint inhibitor(ICI) therapies are a standard treatment for advanced non-small-cell lung cancer(NSCLC). However, the beneficial effects are limited to a small subset of patients. Primary resistance to ICIs has been attributed to various kinds of suppressive immune regulatory cells in tumor-microenvironment. Different strategies have thus been explored to escape from immune evasion by depleting and/or inactivating these regulatory cells. Given the immune-modulating effects of low doses of cyclophosphamide and adriamycin (CA), we assessed the efficacy of CA induction therapy to modulate the antitumor effect of the nivolumab in advanced NSCLC. Methods: This was a single center, open-label, single arm, phase II trial of nivolumab after CA induction therapy in previously treated advanced non-squamous NSCLC with PD-L1<10%. Patients received cyclophosphamide(500mg/m2) and doxorubicin(50mg/m2) every 3weeks with additional nivolumab 360mg from the start of second cycle. After 4 cycles of induction therapy nivolumab 480mg was administered every 4weeks until disease progression or unacceptable toxicity. Assessments were performed every 4 weeks. The primary end point was objective response rate (ORR); secondary end points were progression-free survival (PFS), overall survival(OS) and safety. Level of various immune cells including myeloid-derived suppressor cells (MDSC), cytotoxic CD8+T-cell and regulatory T cells were measured by flow cytometry. Results: A total of 22 patients were enrolled; the median age, 61 years old; female, 81%; adenocarcinoma histology, 76.2%; and current or former smoker, 26.9%. The ORR and disease control rate (DCR) were 9.1% (95% confidence interval [CI], 1.9 -26.1)) and 22.7% (95% CI, 9.2-42.9) respectively. The median PFS and OS were 2.4 months (95% CI, 1.3-3.5) and 11.6 months (95% CI, 5.3-18.0) respectively. Though there were no significant safety signals during the trial, 72% of patients had grade 3 or 4 hematologic toxicities including neutropenia and anemia during CA combination. Regarding MDSC (HLA-DR-Lin-CD11b+CD33+) level, two patients with good response correlatively maintained the low ratio (<1) of MDSC to CD8+T-cell throughout the treatment. Conclusions: Our study didn’t meet the primary endpoint. However, CA induction prior to nivolumab showed an immune-modulating potential by decreasing MDSC in two responders. Further augmentation studies for enhancing ICIs response are warranted. As more patients gets ICIs, combination strategy with various immune modulator harbors great potential to eliminate the immunosuppressive mechanism within the tumor microenvironment architecture. Citation Format: Beung-Chul Ahn, Hyae Young Kim, Geon Kook Lee, Sang-Jin Lee, Ji-Eun Hwang, Kyoungsuk Kwon, Youngjoo Lee, Ji-Youn Han. Nivolumab after cyclophosphamide and doxorubicin induction therapy in previously treated advanced non-squamousl non-small cell lung cancer with PD-L1<10% [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5539.

Real-world biomarker testing trends in metastatic non-small cell lung cancer (NSCLC).

e18728 Background: NSCLC is now recognized as not one disease, but many—differentiated by an increasing number of molecular targets. About 50% of patients with advanced nonsquamous NSCLC have a targetable driver mutation. We retrospectively assessed biomarker testing trends in a large community oncology practice to identify evolving real-world testing rates and patterns in the areas of methodology, specimen types, and vendors. Methods: Natural-language processing queries were used to extract data from biomarker testing reports of patients diagnosed with stage IV NSCLC in 2015-2019. Tests were included if done within 1 year of diagnosis and were classified as NGS panels (20+ genes) or targeted single-gene tests. Results: Records of 587 patients were included. Over the 5-year study window, testing rates increased for all 6 mutations analyzed (Table). In 2015, only ALK, ROS1, and EGFR were profiled in our data (n = 20 patients), all using targeted single-gene tests. The use of multigene panels increased steadily over time, constituting the majority by 2019. MET, RET, and NTRK were tested almost exclusively using NGS panels (data beginning in 2016). Tissue-only specimens were used for 93.8% of patients diagnosed in 2015, while tissue plus blood were used in 6.3%. Blood-only samples began appearing in our data in 2016, making up 7% of patients. By 2019, the use of blood tests had increased substantially, to 47% of patients, although tissue-only remained the most common type (54%). While blood testing has become more popular, it is often still performed with tissue tests. The primary testing methods used in 2015-2017 were FISH for ALK and ROS1; NGS for MET, NTRK, and RET; and Sanger or NGS for EGFR. By 2018, NGS had become the predominant test method across all 6 biomarkers. During 2015-2016, several vendors were used for testing, with a very segmented market for ALK and EGFR tests. By 2019, the market had aligned to a few key vendors for the majority of tests. In 2016, the top 5 vendors did 76% of 180 total tests, which increased to 93% of 1880 tests in 2019. Almost all blood testing in our data was performed by a single vendor. Conclusions: Testing rates for ALK, ROS1, and EGFR were more consistent than those for MET, RET, and NTRK throughout the study window, possibly because of earlier availability of tests and treatments for these biomarkers. NGS was more available by the time MET, RET, and NTRK became established as actionable biomarkers, explaining the earlier use of panels. A limitation is that nearly 75% of the data are from the final 2 years. These results, however, represent notable testing trends from a large practice and illustrate the expanding application of molecular testing in community oncology.[Table: see text]

Platinum-free chemotherapy in the new era of immunotherapy: A phase II study of camrelizumab combined with apatinib and albumin paclitaxel in advanced non-squamous NSCLC (CAPAP-lung).

9034 Background: Cytotoxic chemotherapy and anti-angiogenic therapy may enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Platinum-containing dual-agent chemotherapy combined with ICIs is the standard first-line treatment for non-small cell lung cancer (NSCLC), however, the optimal combination regimen remains unclear. The adverse effects of platinum-based chemotherapy are relatively serious, whether platinum chemotherapy can be eliminated in the first-line treatment of non-small cell lung cancer is a hotspot and difficulty in current research. Based on these results, we initiated CAPAP-lung study, which is a single-arm, multicenter Phase II trial to evaluate the efficacy and safety of Camrelizumab in combination with apatinib and albumin paclitaxel without platinum as the first-line therapy for non-squamous non-small cell lung cancer. Methods: Patients diagnosed with ⅢB-IV non-squamous NSCLC without EGFR and ALK sensitive mutations received Camrelizumab (200mg/3w) in combination with Albumin Paclitacxel (135mg/m2, d1, d8/3w, 4-6 cycles) and Apatinib (250mg Qd po for 5 days, resting for 2 days every week). From August 2020 to February 2022, 54 of the planned 63 patients have been enrolled. The primary endpoint is progression-free survival(PFS), and secondary endpoints were overall survival (OS), duration of Response (DOR), objective response rate (ORR), and disease control rate (DCR) assessed by RECIST v1.1. This study is registered with ClinicalTrials.gov, NCT04459078 (follow-up is ongoing). Results: The data for a total of 38 patients out of 54 enrolled patients were evaluable. Median PFS was 10.97 mo (95%CI 7.1-NR).The objective response rate (ORR) and disease control rate (DCR) were 71.1% (27/38, 95%CI 53.9-84.0) and 97.4% (37/38, 95%CI 84.6-99.9), respectively. The incidence of grade 3 and worse treatment-related adverse events was acceptable, with grade 3 events in 25(46.3%) patients and grade 4 events in 3(5.6%) patients. The most common grade 3 treatment-related adverse events were decreased neutrophil count (8 [14.8%]), liver function damage (9 [16.7%]), rash (3 [5.6%]), and decreased white blood cell count (3 [5.6%]). Conclusions: Camrelizumab combined with albumin paclitaxel and apatinib showed encouraging antitumor activity with an acceptable safety profile for the first-line treatment of advanced lung adenocarcinoma. Clinical trial information: NCT04459078.

Afatinib (Afa) + bevacizumab (Bev) versus afatinib alone as first-line treatment of patients with EGFR-mutated advanced non-squamous NSCLC: Primary analysis of the multicenter, randomized, phase II study—AfaBev-CS study.

9112 Background: Adding Bev to erlotinib prolonged PFS in NEJ026 and CTONG1509 trials, but limited data are available adding Bev to a second-generation EGFR-tyrosine kinase inhibitor. AfaBev-CS is a Japanese no-profit, randomized, open-label, multicenter phase II trial of Afa plus Bev vs Afa alone as first-line treatment for EGFR-mutated advanced NSCLC. Methods: This study enrolled untreated pts of advanced non-squamous NSCLC harboring EGFR sensitizing mutation (Del19 or L858R) and without symptomatic brain metastases. 100 eligible pts were randomized in a 1:1 ratio to receive either Afa (30 mg, daily) plus Bev (15 mg/kg, every 3 weeks) (AfaBev arm) or Afa (40 mg, daily) monotherapy (Afa arm), and stratified according to stage, EGFR mutation status and institution. The primary endpoint was PFS and the secondary endpoints were OS, tumor response and time to treatment failure. The sample size was set in terms of feasibility. The power is greater than 50% under the assumptions of a median PFS of 12 months for the Afa arm and HR of 0.6 for the AfaBev arm, with an accrual of 2.5 years and a minimum planned follow-up period of 2 years with the type 1 error of 0.05 (two-sided). Results: Between August 2017 and September 2019, 100 pts were enrolled (each arm, 50 pts). At a median follow-up of 31.3 months for all randomized pts, total 69 events occurred. Median PFS was 16.3 months for AfaBev arm and 16.1 months for Afa arm, with a hazard ratio (HR) of 0.865 (95%CI, 0.539 – 1.388; loglank p = 0.5476). In subgroup analysis, pts < 70 years old (HR 0.347) and pts with brain metastasis (HR 0.353) showed better trend of PFS in AfaBev arm. On the other hand, pts ≥ 70 years old (HR 1.738) and pts without brain metastasis (HR 1.196) did not show better trend in AfaBev arm. In terms of OS, result was immature because number of events was still small. Objective response rate was 77.6% in AfaBev arm and 72.0% in Afa arm. Severe adverse events were observed in 11 pts for each arm. Grade 3 or more diarrhea, hypertension, rash acneiform, paronychia and stomatitis were frequently observed in AfaBev arm. Pneumonitis was not observed for AfaBev arm and observed in 3 (6.0%) for Afa arm, and grade 3 in one patient. Conclusions: This study failed to show the efficacy of AfaBev arm for improving PFS in untreated pts with EGFR mutated non-squamous NSCLC. In pts < 70 years old, Afa plus Bev might be promising. Clinical trial information: jRCTs061180006.

Open-label, randomized, multicenter, phase 3 study evaluating trastuzumab deruxtecan (T-DXd) as first-line treatment in patients with unresectable, locally advanced, or metastatic non–small cell lung cancer (NSCLC) harboring HER2 exon 19 or 20 mutations (DESTINY-Lung04).

TPS9137 Background: The standard of care (SOC) for patients with oncogene driver subsets of metastatic NSCLC is guided by specific molecular characterization and includes immunotherapy, chemoimmunotherapy, and matched targeted therapies. Although targeting HER2 has transformed the care of patients with breast and gastric cancers, there is currently no approved HER2-targeted therapy for NSCLC. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients (median, 2 prior lines) with unresectable or metastatic HER2-mutant NSCLC, T-DXd demonstrated durable and robust anticancer activity, with a confirmed objective response rate (ORR) of 55% and median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of 9.3, 8.2, and 17.8 months, respectively (Li et al. N Engl J Med. 2022). Given the efficacy observed in later-line settings and the unmet need for targeted therapies in patients with HER2-mutant NSCLC, evaluating the efficacy of T-DXd in the first-line setting vs SOC is important to determine the optimal treatment. Here we describe the phase 3 DESTINY-Lung04 trial (NCT05048797) evaluating T-DXd as a first-line treatment in patients with NSCLC harboring HER2 mutations. Methods: DESTINY-Lung04 is an open-label, randomized, multicenter, phase 3 study evaluating the efficacy and safety of first-line T-DXd vs SOC in patients with unresectable, locally advanced (not amenable to curative therapy), or metastatic nonsquamous NSCLC with HER2 exon 19 or 20 mutations (detected in tissue or circulating tumor DNA). Patients must be naive to systemic therapy with palliative intent in the locally advanced or metastatic disease setting and must not have tumors with EGFR or other targetable oncogenic alterations. Patients with brain metastases must have previously completed local therapy. Patients will be randomized to receive T-DXd or SOC (platinum [investigator’s choice of cisplatin or carboplatin], pemetrexed, and pembrolizumab). The primary endpoint is PFS defined by RECIST version 1.1 per blinded independent central review (BICR). Secondary endpoints include OS, ORR, and DOR (by RECIST 1.1 per BICR and investigator), investigator-assessed PFS (by RECIST 1.1) and time to second progression or death (per local standard clinical practice), central nervous system PFS (by RECIST 1.1 per BICR), landmark PFS at 12 months (by RECIST 1.1 per BICR and investigator), and landmark OS at 24 months. Safety and tolerability, pharmacokinetics, immunogenicity, and patient-reported outcomes, including pulmonary symptoms and tolerability, will be assessed. Clinical trial information: NCT05048797.

Clinical efficacy and safety of the BAT1706 (proposed bevacizumab biosimilar) compared with reference bevacizumab in patients with advanced nonsquamous NSCLC: A randomized, double-blind, phase III study.

9041 Background: A Randomized, Double-blind, Phase III Study was conducted to confirm clinical similarity between BAT1706, a proposed biosimilar to reference bevacizumab, and EU-bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Methods: Patients were randomized 1:1 to BAT1706 plus paclitaxel and carboplatin (Arm A) or EU-bevacizumab plus paclitaxel and carboplatin (Arm B) given three weeks for 6 cycles, followed by maintenance therapy with BAT1706 or EU- bevacizumab. The primary endpoint was overall response rate at Week 18 (ORR18). Secondary endpoints included ORR at Week 6 and 12, best ORR, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: A total of 651 patients were randomized: BAT1706 (n = 325) or EU- bevacizumab (n = 326). In total, 649 randomized patients (BAT1706 (n = 325) or EU- bevacizumab (n = 324)) received at least one cycle of combination treatment. The median duration of therapy was 29.1 weeks (ranging from 3.0 to 62.1 weeks) in the Arm A and 27.0 weeks (ranging from 3.0 to 53.9 weeks) in the Arm B. The extent of exposure to BAT1706 and EU- bevacizumab was similar between these two arms. Overall, the proportion of patients achieving an ORR by Week 18 was comparable across Arm A and B (48.0% and 44.5%). The ORR risk ratio of 1.08 with 90% CI (0.94, 1.24) and the ORR risk difference of 0.03, with 95% CI (-0.04, 0.11) were within pre-specified equivalence margin. In addition, the multivariate-adjusted risk ratio was 1.07, with a 90% CI (0.93, 1.22). The ORR18 risk difference between BAT1706 and EU- bevacizumab was 0.03, with the 2-sided 95% CI (-0.04, 0.11) that fell entirely within pre-specified equivalence margin. In addition, the multivariate-adjusted risk difference was 0.03, with a 95% CI (-0.04, 0.11). The hazard ratio stratified for time to PFS was 0.915 and the PFS rate at 12 months was 20.7% versus 21.8%. At the end of the study, there were no significant differences between both the treatments. The incidence of treatment-emergent adverse events (TEAEs) and study drug-related TEAEs was similar between these two arms. Overall, the safety profiles of BAT1706 were consistent with that of EU- bevacizumab, no new safety signals or noticeable trends were observed. The mean serum concentrations were comparable between BAT1706 and EU- bevacizumab over the entire sampling interval both in pre-dose and post-dose. The incidence of positive anti-drug antibodies results was low (≤5%) and decreased over time in both treatment arms. No patient was detected to have positive neutralizing anti-drug antibody result during the study. Conclusions: BAT1706 demonstrated clinical equivalence to reference EU-bevacizumab in terms of efficacy, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT03329911.

Outcomes of sintilimab plus pemetrexed and platinum (SPP) according to stage of disease in patients (pts) with locally advanced or metastatic nonsquamous NSCLC (AMnsqNSCLC) in the phase 3 ORIENT-11 study.

e21157 Background: In ORIENT-11, first-line (1L) SPP improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and duration of response (DoR) compared with placebo plus pemetrexed-platinum (PPP) in pts with AMnsqNSCLC. We report outcomes from ORIENT-11 (NCT03607539) for pts treated with SPP with stage III (b & c) compared with stage IV disease. Methods: Pts with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR/ALK alterations were randomly assigned to SPP (n = 266) or PPP (n = 131), stratified by PD-L1 expression, platinum-chemotherapy and sex. Primary endpoint was PFS (RECIST v1.1). Secondary endpoints included OS, ORR, DoR and safety. Kaplan-Meier method was used to analyze median PFS, OS and DoR. Stratified Cox model was used to analyze the hazard ratio (HR) of SPP vs. PPP. Clopper-Pearson method was used to calculate the 95% confidence intervals (CI) of ORR for each group. Miettinen-Nurminen method was used to analyze 95% CI of ORR difference between SPP and PPP. Data cutoff for OS data was September 15, 2021, providing a median follow-up of 30.8 months. Cutoff for other data was November 15, 2019, providing a median follow-up of 8.9 months. Results: 21 pts (7.9%) receiving SPP had stage III disease and 245 pts (92.1%) had stage IV disease. Baseline sex, age and PD-L1 expression ≥1% were similar between subgroups (Table). There were differences between subgroups in number of pts receiving carboplatin and ECOG performance status at baseline. PFS, OS, ORR and DoR outcomes were comparable between pts with stage III and stage IV disease based on the ad-hoc analyses. Any-grade adverse events (AEs) (100.0% vs. 99.6%) and AEs of Grade ≥3 (57.1% vs. 62.0%) were similar in pts with stage III and stage IV disease. Conclusions: In ORIENT-11, outcomes for pts receiving SPP as 1L therapy in AMnsqNSCLC with stage III and stage IV disease were comparable. Clinical trial information: NCT03607539. [Table: see text]

Addition of Bevacizumab to Erlotinib as First-Line Treatment of Patients With EGFR-Mutated Advanced Nonsquamous NSCLC: The BEVERLY Multicenter Randomized Phase 3 Trial

IntroductionAdding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC. MethodsEligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17. ResultsFrom April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2–18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2–10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47–0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination. ConclusionsThe addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues.

A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non-small cell lung cancer.

9019 Background: Based on IMPOWER 150, atezolizumab in combination with bevacizumab and platinum-based chemotherapy has been the first-line treatment for advanced non-squamous NSCLC with negative driver genes. AK112 is a global first-in-class anti-PD-1/VEGF bi-specific antibody developed by Akesobio. Preclinical and clinical studies have indicated that AK112 possess potential anti-tumor efficacy in solid tumors. Therefore, we aimed to assess the efficacy and safety of AK112 in combination with chemotherapy for patients with advanced NSCLC. Methods: This was an open-label, multi-center phase II study evaluating the efficacy and safety of AK112 in combination with chemotherapy in pts with advanced NSCLC. Enrolled pts were divided into three cohorts: Previously untreated advanced NSCLC pts with wide-type EGFR/ALK (Cohort 1), pts with EGFR mutations who had failed prior EGFR-TKI therapies without T790M mutation or failed osimertinib treatment (Cohort 2), and pts who progressed after anti-PD-1/L1 and platinum-based chemotherapy (Cohort 3). Pts were treated with 10mg/kg or 20mg/kg AK112 once every 3 weeks in combination with carboplatin and pemetrexed or carboplatin and paclitaxel for Cohort 1/2, and docetaxel for Cohort 3. Primary endpoint was ORR as assessed by investigator per RECIST v1.1. Results: 133 pts were enrolled from Feb 03, 2021 to Dec 31, 2021 and received AK112 plus chemotherapy (44 received AK112 10 mg/kg and 89 received AK112 20 mg/kg). As of Dec 31, 2021, in cohort-1, among 26 evaluable pts with squamous cell carcinoma, 20 partial response and 6 stable disease were observed for a 76.9% ORR and a 100.0% DCR, median DOR and median PFS was not reached while 6-month PFS rate was 86.2%. In Cohort-2, among 19 evaluable pts, 13 partial response and 5 stable disease were observed for a 68.4% ORR and a 94.7% DCR while median DOR was 5.5 months, and median PFS was 8.3 months. In Cohort-3, among 20 evaluable pts, 8 partial response and 8 stable disease were observed for a 40.0% ORR and a 80.0% DCR, median DOR and median PFS was not reached while 6-month PFS rate was 71.1%. Treatment emergent adverse events (TEAE) occurred in 86.5% (115/133) of the pts, and grade ≥3 AEs occurred in 28.6% (38/133) of pts including two deaths. Most common AE (incidence ≥ 5%) included alanine/aspartate aminotransferase increased, epistaxis, anemia, vomiting, nausea, rash, leukopenia, thrombocytopenia, and neutropenia. Treatment discontinuation due to AE occurred in 3.0% (4/133) of the pts. Conclusions: AK112 plus chemotherapy has shown a promising anti-tumor efficacy in each cohort and warrants potentially superior safety in comparison to anti-PD-(L)1 and anti-VEGF combination therapies in advanced NSCLC. PFS and ORR were also significantly improved with AK112 plus chemotherapy. Therefore, phase III registration studies of AK112 plus chemotherapy in advanced NSCLC will be initiated in 2022. Clinical trial information: NCT04736823.

Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study

IntroductionTo evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations. MethodsWe conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review. ResultsBetween January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700–1.060, 95% confidence interval: 0.531–1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm. ConclusionsThis study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment.

Efficacy and safety of maintenance immune checkpoint inhibitors with or without pemetrexed in advanced non-squamous non-small cell lung cancer: a retrospective study

BackgroundAdvanced non-squamous non-small cell lung cancer (NS-NSCLC) patients without driver gene mutations are usually treated with immune checkpoint inhibitors (ICIs) plus pemetrexed as maintenance therapy after first-line ICIs plus 4–6 cycles of pemetrexed/platinum. Some patients in the real world receive ICIs monotherapy as maintenance therapy. No clinical study has compared the efficacy and safety of ICIs with or without pemetrexed as maintenance therapy.MethodsWe performed a retrospective study analyzing clinical data of patients with NS-NSCLC who were diagnosed in Zhejiang Cancer Hospital from September 2018 to May 2021 and received maintenance therapy after 4–6 cycles of ICIs plus pemetrexed/platinum. Patients were divided into ICIs plus pemetrexed group and ICIs monotherapy group. Progression Free Survival 1 (PFS1) and PFS2, defined as the interval from the date of initial treatment and maintenance therapy to the date of systemic progression/death or the last follow-up, respectively.ResultsA total of 120 patients received ICIs with or without pemetrexed as maintenance therapy. Eighty-two patients received ICIs plus pemetrexed as maintenance therapy, and 38 patients received ICIs monotherapy. There were no statistically significant difference in median PFS1 between the ICIs monotherapy group and ICIs plus pemetrexed group (12.00 months vs. 12.07 months, P = 0.979). Among patients with PD-L1 TPS < 1%, the median PFS1 was worse with ICIs monotherapy (9.50 months vs. 14.20 months, P = 0.039). Among patients with PD-L1 TPS ≥50% or 1–49%, the median PFS1 in both groups was not statistically significant (P = 0.866, P = 0.589, respectively). Results for median PFS2 were similar to median PFS1, with statistically significantly different only in patients with PD-L1 TPS < 1% (P = 0.008). The 2-year survival rates of the two groups were similar (66.7% vs. 69.5%, P = 0.812). The incidence of fatigue was significantly higher in the ICIs plus pemetrexed group (P = 0.023).ConclusionsICIs with or without pemetrexed can be used as maintenance therapy after first-line ICIs plus 4–6 cycles of pemetrexed/platinum in patients with advanced NS-NSCLC based on PD-L1 expression.

Barriers in precision medicine implementation among Advanced Nonsquamous Cell Lung Cancer-patients: A Real-World Evidence Scenario

ABSTRACT Background Precision oncology has a prominent role in nonsquamous non-small cell lung cancer (nsNSCLC) treatment progress; however, its access in a real-world scenario might be limited. Objective To investigate the time spent in nsNSCLC molecular profile evaluation and its influence on clinical decisions. Methods nsNSCLC patients who underwent molecular testing in a private referral Brazilian center between November 2015 and February 2020 were identified. The interval from nsNSCLC diagnosis to the characterization of the molecular profile was determined. Other outcomes, focusing on the biomarker tissue journey, were also assessed. Results In this cohort (n = 78), the median time between the advanced nsNSCLC diagnosis and biomarker characterization was 40.5 days (range, 29.5–68.5). The median interval between the diagnosis and the test request was longer than the interval between the request and the results (respectively 29.0 versus 12.0 days; p < 0.001). At the treatment initiation, 51% (36/71) of the patients who received any systemic therapy did not have their driver mutations panel results available. But on these, 42% (15/36) had a targetable alteration identified later on. Among patients harboring a targetable alteration, only 46% (n = 13/28) received a tyrosine kinase inhibitor (TKI) as first-line therapy. The median time to the TKI initiation was even longer than the median time to all treatment initiation (92.0 versus 40.0 days). Conclusions Our data show a long median time from advanced nsNSCLC diagnosis and the availability of the biomarker testing in medical practice, which impacted the choice of a non-personalized therapy as the first-line.

Cost-effectiveness analysis of sintilimab + chemotherapy versus camrelizumab + chemotherapy for the treatment of first-line locally advanced or metastatic nonsquamous NSCLC in China

Background and objective Sintilimab is a selective PD-1 inhibitor with efficacy in advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) patients. This study evaluated the cost-effectiveness of sintilimab + chemotherapy versus camrelizumab + chemotherapy as the first-line treatment for locally advanced or metastatic nonsquamous NSCLC in Chinese patients. In addition, this study aimed to reveal the impact of the reference treatment choice on the incremental cost-effectiveness ratio (ICER) results. Methods A partitioned survival model (PSM) with three health states was constructed in a 3-week cycle with a lifetime horizon from the Chinese healthcare system perspective. Anchored matching adjusted indirect comparison was used for survival analyses based on individual patient data from Orient-11. Sintilimab + chemotherapy was chosen as the reference treatments in scenarios 1 and 2, while the camrelizumab + chemotherapy was chosen as the reference treatments in scenario 3. The utility values of different health states were derived from the patient-level European Organization for Research and Treatment Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) scores by mapping to the EQ-5D-5L, and QALYs were calculated as the health outcomes. One-way deterministic sensitivity analysis (DSA) and probability sensitivity analysis (PSA) were performed to explore model uncertainty. Results Compared to camrelizumab + chemotherapy, sintilimab + chemotherapy was associated with higher effectiveness (incremental QALYs ranged from 0.13–0.62) and lower total costs (incremental costs ranged from $1,099–$5,201), resulting in an ICER ranging from $6,440–$8,454/QALY. Conclusions Sintilimab + chemotherapy is a cost-effective option compared with camrelizumab + chemotherapy as the first-line treatment for locally advanced or metastatic nonsquamous NSCLC in China.

Cost-Effectiveness of Bevacizumab Biosimilar LY01008 Combined With Chemotherapy as First-Line Treatment for Chinese Patients With Advanced or Recurrent Nonsquamous Non-Small Cell Lung Cancer.

Objective: To investigate whether LY01008, a locally developed bevacizumab biosimilar agent, is appropriate for widespread use among Chinese advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC) patients, our current study was designed to evaluate the cost-effectiveness of first-line LY01008 combined with platinum-doublet chemotherapy versus chemotherapy alone from the perspective of the Chinese healthcare system. Material and Methods: This economic evaluation designed a Markov model to compare the healthcare cost and quality-adjusted life-year (QALY) of first-line LY01008 combined with chemotherapy versus first-line chemotherapy. Transition probabilities, including disease progression, survival, and adverse event (AE)-related discontinuation of first-line treatment, were estimated using data from the clinical trials. Costs and health utilities were derived from local databases, hospitals, and published literature. Our base case analysis and scenario analysis focused on the cost-effectiveness of chemotherapy combined with a clinical trial dosage (15 mg/kg every 3-week cycle) and a real-world dosage (7.5 mg/kg every 3-week cycle) of LY01008, respectively. Results: In the base case analysis, first-line LY01008 combined with chemotherapy was associated with an increase of 0.48 QALYs in effectiveness and an increase of CNY 189,988 (US$ 26,240) in healthcare costs compared with first-line chemotherapy, resulting an incremental cost-effectiveness ratio (ICER) of CNY 375,425 (US$ 54,430)/QALY. In the scenario analysis, first-line LY01008 combined with chemotherapy was associated with a mean healthcare cost of CNY 265,060 (US$ 38,429), resulting an ICER of CNY 221,579 (US$ 32,125/QALY) between first-line LY01008 combined with chemotherapy versus first-line chemotherapy. The parameters that determine the cost of LY01008 have the greatest impact on the cost-effectiveness results. Conclusion: From the perspective of the Chinese healthcare system, first-line LY01008 at a real-world dosage combined with chemotherapy is likely to represent a cost-effective strategy compared with first-line chemotherapy alone for Chinese advanced or recurrent nonsquamous NSCLC patients.

53P Second-line treatment in advanced non-squamous (NS) non-small cell lung cancer (NSCLC) patients in Spain, analyzed in the Thoracic Tumor Registry (RTT)

Non-small cell lung cancer (NSCLC) accounts for the vast majority of all diagnosed lung cancers. From a histological point of view, approximately 70% to 78% of NSCLC are considered non-squamous (NS). Our analysis aimed to describe the clinical, epidemiological characteristics and survival of Spanish patients suffering from advanced NS NSCLC, treated in second line included in the RTT of the Spanish Group of Lung Cancer. 2342 patients with advanced NS NSCLC in second line were included. The median age was 67 years. 63.4 % were men. 97% of them were White. 41.7% were former smokers and 35.7% were active smokers. ECOG performance status was 0 in 32.2% and 1 in 58.7%. Most common site of metastasis was lung in 41.7%, bone in 36%, and adrenal glands in 15.6% of patients. In overall population a median progression-free survival (PFS) time of 8.1 months (4.7-13.5 m) was observed. A median overall survival (OS) time of 22.1 m (11.6-45.8 m) A total of 145 (5.8%) patients had been treated with nintedanib (N). The median PFS for patients with N treatment was 8.3 months (5.6 - 16.2 months) and for patients without was 8.1 months (4.7 - 13.5). The probability of PFS at 6, 12 and 24 m was 66.1% (64.0% - 68.0%), 29.8% (27.8% - 31.7%) and 8.2% (7.1% - 9.4%), respectively, in patients without N treatment, and 70.8% (62.4% - 77.7%), 32.8% (25.1% - 40.7%) and 11.7% (8.0% - 17.7%) in patients with N treatment. The median OS with N was 22.4 m (13.5-39.5 m) and for patients without was 22.1 m (11.6 - 45.8 m). The OS at 6, 12 and 24 m was 98.6% (94.5% - 99.6%), 80.7% (73.2% - 86.4%) and 45.5% (36.9% - 53.7%), respectively in patients with N and 93.2% (92.0% - 94.1%), 73.9% (72.0% - 75.7%), and 47.1% (44.9% - 49.3%) in patients without. The results of our analysis described the largest and most comprehensive series of NS NSCLC in the European population. Most patients included in the analysis were men and former or current smokers. The survival probability at 6, 12 and 24 months is slightly better in patients treated with nintedanib versus the overall population.

4MO Final overall survival (OS) data of sintilimab plus pemetrexed (SPP) and platinum as first-line (1L) treatment for locally advanced or metastatic nonsquamous NSCLC (AMnsqNSCLC) in the phase III ORIENT-11 study

In ORIENT-11, 1L SPP significantly improved progression-free survival (PFS) compared with placebo plus pemetrexed-platinum (PPP) in patients (pts) with AMnsqNSCLC. The study met the primary endpoint of PFS at interim analysis (15NOV2019). Updated OS analysis showed OS benefit. Here we report final OS from ORIENT-11 (Clinical Trials.gov: NCT03607539) using a September 15, 2021 data cutoff.

Generalizability of ORIENT-11 trial results to a USstandard-of-care cohort with advanced non-small-cell lung cancer.

Aim: This retrospective study estimated efficacy and safety of sintilimab+pemetrexed +platinum (SPP) versus placebo+pemetrexed+platinum (PPP)in untreated locally advanced/metastatic, nonsquamous non-small-cell lung cancer (NSCLC), after adjusting each ORIENT-11 trial patient's contribution to ORIENT-11 data based on characteristics of a targetUS population. Materials & methods: The targetUS population (n=557) was selected from a real-world deidentified advanced NSCLC database based on key ORIENT-11 eligibility criteria. Inverse probability weightsfor ORIENT-11 patients (n=397) relative to US patients were calculated. Efficacy and safety of SPP versus PPP were adjusted by inverse probability weights. Results: After adjustment, progression-free survival remained superior for SPP. Other efficacy and safety outcomes were consistent. Conclusion: These results provide evidence on how the effects observed with SPP in ORIENT-11 could translate to a US population with untreated locally advanced/metastatic nonsquamousNSCLC.

Camrelizumab Plus Apatinib in Treatment-Naive Patients With Advanced Nonsquamous NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 2 Trial

IntroductionOur preclinical work suggests that low-dose angiogenesis inhibition could potentiate programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade. In a cohort of our multicenter phase 1b and 2 study (NCT03083041), promising antitumor activity was observed with camrelizumab plus low-dose apatinib in chemotherapy-pretreated patients with advanced nonsquamous NSCLC. We hereby reported the results in treatment-naive patients (cohort 4) from the same study. MethodsEligible patients had untreated advanced nonsquamous NSCLC with a high tumor mutational burden (TMB) (tissue TMB >10 mutations per megabase or blood TMB ≥1.54 mutations per megabase) and without sensitizing EGFR or ALK alterations. Patients received camrelizumab 200 mg intravenously every 2 weeks plus apatinib 250 mg orally once daily. The primary end point was the objective response rate (ORR) per investigator. ResultsA total of 25 patients were enrolled and treated. A total of 10 (40.0%) confirmed partial responses and 13 (52.0%) stable diseases were observed. The ORR was 40.0% (95% confidence interval [CI]: 21.1–61.3) and disease control rate was 92.0% (95% CI: 74.0–99.0). With a median follow-up of 19.5 months, the median progression-free survival was 9.6 months (95% CI: 5.5–not reached), whereas the overall survival was not reached; the median duration of response was 15.6 months (95% CI: 3.8–not reached). Similar ORR and progression-free survival were observed regardless of PD-L1 tumor proportion score (≥1% versus <1%). The most common treatment-related grade 3 or higher adverse events were increased gamma-glutamyltransferase (24.0%), increased alanine aminotransferase (16.0%), and abnormal hepatic function (16.0%). ConclusionsFrontline camrelizumab plus low-dose apatinib exhibited promising clinical activity with acceptable safety in patients with advanced nonsquamous NSCLC regardless of PD-L1 expression.