First-line Treatment Of Advanced Non-small Cell Lung Cancer Research Articles

Stage-specific efficacy of osimertinib in treatment-naïve EGFR-mutant non-small cell lung cancer according to baseline genetic alterations in circulating tumor DNA.

The impact of clinical stage on the effectiveness of osimertinib for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) remains unexamined. We investigated osimertinib therapeutic efficacy variation between stage IVA or lower and stage IVB EGFR mutation-positive lung cancers, focusing on differences in pretreatment co-occurring genetic alterations in circulating tumor DNA. This was a secondary analysis of the ELUCIDATOR study, a multicenter prospective observational study in Japan that assessed the mechanisms underlying resistance to osimertinib as a first-line treatment for advanced NSCLC with EGFR mutations. We compared the progression-free survival (PFS), overall survival (OS), and pretreatment co-occurring genetic alterations detected in plasma between patients with stages IVA (n = 83) and IVB disease (n = 84). Multivariate analysis of PFS and OS revealed that stage IVB was associated with a poor prognosis (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.36-3.04, p < 0.001, HR: 2.35, 95% CI: 1.45-3.90, p < 0.001, respectively). Pre-osimertinib treatment, significantly more TP53- (52.4% vs. 27.7%, p = 0.002), EGFR amplification- (58.3% vs. 23.2%, p < 0.001), and MET amplification-positive cases (22.6% vs. 7.2%, p = 0.008) were found among stage IVB than among stage IVA or lower cases. Patients with EGFR-positive NSCLC in stage IVB exhibited significantly shorter PFS and OS than those in earlier stages when treated with first-line osimertinib. The prevalence of baseline TP53 mutations, EGFR amplification, and MET amplification in plasma were significantly higher in stage IVB cases, implicating them in the worse outcomes of this group.

Diverse clinical outcomes for the EGFR‑mutated and ALK‑rearranged advanced non‑squamous non‑small cell lung cancer.

EGFR and ALK are key driver mutations in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors are recommended as the first-line treatment for advanced NSCLC with driving oncogenes because they have fewer side effects and provide better disease control than chemotherapy. The present retrospective analysis aimed to investigate how altered driver genes impact cancer outcomes and clinical presentation. A total of 628 patients with advanced-stage NSCLC and documented EGFR and ALK mutations were enrolled at Changhua Christian Hospital in Taiwan between August 2011 and January 2021. EGFR mutations were identified by PCR. ALK rearrangements were identified by immunostaining. Patients without EGFR or ALK mutations were labeled as wild-type (WT). EGFR mutation was detected in 446 (71.02%) patients, ALK rearrangement in 36 (5.73%) patients and WT in 146 (23.25%) patients. EGFR mutations resulted in higher frequency of lung, brain and multiple extrapulmonary metastases than ALK rearrangement. The ALK group exhibited the longest median overall survival (OS), followed by EGFR and WT groups (ALK: 51.60±13.32, EGFR: 24.03±1.22 and WT: 19.63±2.43 months, respectively; P=0.011). In patients with brain metastases, ALK group had a longer median OS than the EGFR group. Because there were few recruited patients with ALK rearrangement, the results were not significant. According to the results of Cox regression model analysis, driver mutations with EGFR and ALK, lower smoking pack-years, younger age, better performance status, no pleural metastasis and fewer extrapulmonary metastases were key prognostic factors. In conclusion, diverse clinical outcomes are driven by different driver mutations. EGFR mutation leads to more extrapulmonary metastases. Median OS was superior in ALK-rearranged NSCLC than EGFR-mutated NSCLC regardless of brain metastases.

Cost-effectiveness analysis of first line pembrolizumab monotherapy for high programmed cell death ligand 1 expressed, advanced non-small cell lung cancer in Japan.

Pembrolizumab monotherapy significantly extends progression-free and overall survival compared to platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC), but also has a significant impact on medical costs. To clarify the health economic evidence for selecting the first-line treatment for patients with stage IV advanced NSCLC with a programmed cell death ligand 1 tumor proportion score of 50% or greater in Japan, we assessed the cost-effectiveness of pembrolizumab monotherapy compared with that of platinum-based chemotherapy. Using a Markov model, the study simulated three health states for patients, based on clinical data and utility values from KEYNOTE-024. Transition probabilities were estimated exponentially. Direct medical costs were calculated according to the 2022 National Health Insurance Medical Fee Points and Drug Price Standards. The outcomes measured included life years, quality-adjusted life years, and incremental cost-effectiveness ratio, with sensitivity analysis performed to evaluate the effect of uncertainties. Pembrolizumab led to an additional 1.58 life years and 1.23 quality-adjusted life years at an additional cost of 7,009,888 Japanese yen (48,448 U.S. dollars [USD]), resulting in incremental cost-effectiveness ratio of 4,436,638 Japanese yen (30,663 USD) per life year and 5,699,096 Japanese yen (39,388 USD) per quality-adjusted life year. Pembrolizumab was deemed cost-effective under a threshold of 7.5million Japanese yen (51,835 USD) per quality-adjusted life year. Pembrolizumab monotherapy is a cost-effective option for the first-line treatment of advanced NSCLC with high programmed cell death ligand 1 expression in Japan, providing valuable health economic evidence for treatment selection.

FURVENT: Phase 3 trial of furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertion mutations (FURMO-004).

TPS8668 Background: EGFR exon 20 insertion mutations (ex20ins) occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (1). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. In FAVOUR, treatment naïve patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations showed preliminary clinical activity with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months when treated with 240 mg daily [QD] of furmonertinib (2). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively and included patients harboring near and far loop mutations. Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients have treatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR ex20ins mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastatic setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression can crossover to furmonertinib cohort. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Han et al., WCLC 2023. Clinical trial information: NCT05607550 .

A phase 2/3 study of fianlimab, cemiplimab, plus chemotherapy versus cemiplimab plus chemotherapy in first-line treatment of advanced non-small cell lung cancer.

TPS8660 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Anti–programmed cell death-1 (PD-1) therapies have improved outcomes in patients with NSCLC; however, most patients do not respond or only respond for a limited time. The combination of cemiplimab (anti–PD-1) and chemotherapy has been studied for the first-line treatment of advanced NSCLC (aNSCLC), regardless of programmed cell death-ligand 1 (PD-L1) status. While the standard of care continues to evolve for NSCLC, one approach to potentially improve outcomes is the combination of checkpoint inhibitors (IO) with chemotherapy. Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab are both high-affinity, fully human IgG4 monoclonal antibody IO therapies that have shown promising clinical activity when combined in patients with aNSCLC in a Phase 1 study (NCT03005782). This ongoing study will further investigate the combination of fianlimab + cemiplimab + chemotherapy. Methods: This is a randomized, multicenter, Phase 2/3 study of fianlimab + cemiplimab + platinum-doublet chemotherapy (chemo) versus cemiplimab + chemo in patients with unresectable stage IIIB/IIIC or stage IV NSCLC irrespective of PD-L1 expression levels (NCT05800015). This study will be conducted globally at approximately 210 sites. Patient eligibility criteria: ≥18 years old; squamous or non-squamous histology with stage IIIB, IIIC, or IV disease; valid PD-L1 result; ≥1 radiographically measurable lesion by computed tomography/magnetic resonance imaging; Eastern Cooperative Oncology Group performance status ≤1; adequate organ and bone marrow function. The Phase 2 portion will be used to determine the fianlimab dose selected for the Phase 3 portion: patients will be randomized 1:1:1 to receive fianlimab high dose + cemiplimab 350 mg + chemo (Arm A), fianlimab low dose + cemiplimab 350 mg + chemo (Arm B), or cemiplimab 350 mg + chemo + placebo (Arm C), Q3W IV. In Phase 3, patients will be randomized 1:1 into one of two treatment arms (either Arm A or Arm B, and Arm C) based on findings from Phase 2. The primary endpoint of Phase 2 is objective response rate (ORR) per blinded independent central review. The primary endpoint of Phase 3 is overall survival. The secondary endpoints include efficacy (ORR, disease control rate, time to tumor response, duration of response, progression-free survival, and overall survival), safety and tolerability, immunogenicity (anti-drug antibodies and neutralizing antibodies against fianlimab or cemiplimab in serum), patient-reported outcomes, and pharmacokinetics. This study and a parallel study of fianlimab + cemiplimab in patients with aNSCLC with tumors expressing PD-L1 ≥50% (NCT05785767) are currently open for enrollment. Clinical trial information: NCT05800015 .

Abstract CT280: FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004)

Abstract Introduction: EGFR exon 20 insertion mutations occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (Musib et al., NACLC 2022). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. Promising preliminary clinical activity was observed in the FAVOUR study testing furmonertinib (240 mg daily [QD]) in patients with treatment naïve locally advanced or metastatic NSCLC, with EGFR exon 20 insertion (ex20ins) mutations showing confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months (Han et al., WCLC 2023). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively, and included patients harboring near and far loop mutations.Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Additional furmonertinib preclinical data in uncommon EGFR mutations, including P-loop and αC-helix Compressing (PACC) and ex20ins mutations will be presented at the AACR 2024 Annual Meeting (Nilsson et al., AACR 2024 Abstract #4174). Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients havetreatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR exon 20 insertion mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastases setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression are eligible to participate in the crossover phase of this trial to furmonertinib therapy. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. Clinical trial information: NCT05607550. Citation Format: Alexander Spira, Byoung Chul Cho, Enriqueta Felip, Edward Garon, Koichi Goto, Melissa Lynne Johnson, Natasha B. Leighl, Antonio Passaro, David Planchard, Sanjay Popat, James Yang, Xiaoqian Lu, Yong Jiang, Jack Huang, Morgan Lam, Marcin Kowanetz, Shirley Wang, John Le, Jerry Hsu, Caicun Zhou. FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004) [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 CT280.

Advances in monotherapy and combination therapy of S-1 for patients with advanced non-small cell lung cancer: a narrative review.

Both domestically and worldwide, non-small cell lung cancer (NSCLC) remain the leading cause of cancer-related death. As a fluorouracil derivative, S-1 which shows good efficacy and with few adverse effects have been widely confirmed in many solid tumors that it can provide a glimmer of hope for advanced NSCLC patients. We performed a review to explore the results of previous clinical studies of S-1 monotherapy as well as combined therapy involving S-1 in patients with advanced NSCLC. A literature search was conducted in Medline and PubMed databases using the keywords "S-1" AND "Advanced lung cancer" OR "Pharmacological mechanism". A number of phase II clinical studies have reported on the favorable efficacy and excellent safety profiles of S-1 monotherapy in first-line or in posterior-line treatment for advanced NSCLC. In regard to S-1 in combination with chemotherapy, a number of phase II/III clinical studies have found the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of these regimens are similar to or better than immunological monotherapy with fewer adverse effects. In the case of S-1 combined with anti-vascular therapy, a number of phase II single-arm clinical studies have found that S-1 combined with bevacizumab, anlotinib and apatinib in advanced NSCLC, exhibits higher antitumor activity, less adverse effects for patients with advanced NSCLC. A phase II single-arm clinical study of gefitinib combined with S-1 had the ORR of 85.7% in the first-line treatment of advanced NSCLC. As for the combination of S-1 and immunotherapy, preliminary results of a phase II retrospective clinical trial demonstrated that the ORR was significantly better with S-1 sequential after immune checkpoint inhibitors (ICIs) than with S-1 alone. The findings indicate promising effectiveness and minimal toxicity with S-1 monotherapy and S-1 containing combined therapy in patients with advanced NSCLC to provide a potential treatment option for advanced NSCLC.

Circulating Osteopontin Predicts Clinical and Radiological Response in First-Line Treatment of Advanced Non-Small Cell Lung Cancer

PurposePembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC).MethodsSeventy-nine patients eligible to pembrolizumab regimens—alone or in combination with chemotherapy—as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS).ResultsHigh Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [−4.46 to −1.01]) and time-to death (−0.13 [−0.20 to −0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = −0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses.ConclusionBaseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC.

PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial

No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.

Adverse event costs associated with first-line therapy for advanced non-small cell lung cancer in the United States: An analysis of clinical trials of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors, such as pembrolizumab, nivolumab, and atezolizumab, have demonstrated substantial survival benefits in patients with advanced non-small cell lung cancer (NSCLC). However, there is limited evidence on their relative safety profiles and adverse event (AE)-related cost burden. OBJECTIVE: To compare the AE management costs of nivolumab plus ipilimumab with and without limited chemotherapy with those of chemotherapy, pembrolizumab plus chemotherapy, and atezolizumab plus chemotherapy in a first-line setting among patients with advanced NSCLC. METHODS: The mean per-patient AE costs were estimated using the incidence of all-cause grade 3/4 AEs with any-grade incidence greater than or equal to 15% and the corresponding costs of AE management in the inpatient setting. AE rates were obtained from individual patient data from the CheckMate 227 and CheckMate 9LA trials for nivolumab plus ipilimumab with/without limited chemotherapy and aggregated data from the KEYNOTE-189 and KEYNOTE-407 trials for pembrolizumab plus chemotherapy and the IMpower130 trial for atezolizumab plus chemotherapy. AE management costs from the third-party payer perspective were estimated based on inpatient medical costs from the 2016 United States Healthcare Cost and Utilization Project National Inpatient Sample. All costs were inflated to 2020 US dollars. RESULTS: Nivolumab plus ipilimumab and nivolumab plus ipilimumab plus limited chemotherapy were associated with lower per-patient grade 3/4 AE costs compared with chemotherapy ($1,708 and $624 lower over the treatment course, respectively). Compared with pembrolizumab plus chemotherapy, nivolumab plus ipilimumab was associated with lower grade 3/4 AE costs in patients with nonsquamous histology (difference: -$4,866) and squamous histology (difference: -$3,795), and nivolumab plus ipilimumab with limited chemotherapy also had lower AE costs for both nonsquamous (difference: -$2,800) and squamous (difference: -$2,753) disease. Similarly, nivolumab plus ipilimumab and nivolumab plus ipilimumab plus limited chemotherapy were also associated with lower AE costs ($11,400 and $8,809 lower, respectively) compared with atezolizumab plus chemotherapy among patients with nonsquamous disease. In particular, nivolumab plus ipilimumab without or with limited chemotherapy were associated with much lower AE costs of hematological AEs compared with chemotherapy and other immune checkpoint inhibitor-based treatments in combination with a full course of chemotherapy. CONCLUSIONS: Nivolumab plus ipilimumab with/without limited chemotherapy was associated with lower AE management costs compared with chemotherapy, pembrolizumab plus chemotherapy, and atezolizumab plus chemotherapy as first-line treatment for advanced NSCLC. The AE cost benefits were largely driven by the lower cost burden for hematological AEs for nivolumab plus ipilimumab with/without limited chemotherapy. DISCLOSURES This study was supported by Bristol-Myers Squibb. The sponsor was involved in all aspects of the work and in the decision to submit the manuscript for publication. Dr Stenehjem has received consulting fees from Bristol-Myers Squibb. Dr Lubinga was an employee of Bristol-Myers Squibb at the time of the study's conduct and holds stock/options. Drs Betts and Wu are employees of Analysis Group, Inc., a consulting company that has received funding from Bristol-Myers Squibb for this research.

Efficacy and safety of EGFR-TKIs in combination with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant non-small-cell lung cancer: a systematic review and meta-analysis

BackgroundFor patients with advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, the suggested course of action is epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Even with a high disease control rate, a majority of patients develop acquired EGFR-TKIs resistance and eventually advance. To increase the benefits of treatment, clinical trials are increasingly exploring the value of EGFR-TKIs combined with angiogenesis inhibitors as a first-line treatment in advanced NSCLC carrying EGFR mutations.MethodUsing PubMed, EMBASE and Cochrane Library, to locate published full-text articles in print or online, a thorough literature search was done from the database's inception to February 2021. Additionally, oral presentation RCTs from ESMO and ASCO were obtained. We sifted out RCTs that used EGFR-TKIs along with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant NSCLC. ORR, AEs, OS, and PFS were the endpoints. Review Manager version 5.4.1 was used for data analysis.ResultsOne thousand eight hundred twenty-one patients were involved in 9 RCTs. According to the results, combining EGFR-TKIs with angiogenesis inhibitors therapy prolonged PFS of advanced EGFR-mutation NSCLC patients on the whole [HR:0.65 (95%CI: 0.59~0.73, P<0.00001)]. No significant statistical difference was identified between the combination group and single drug group in OS(P=0.20) and ORR (P=0.11). There are more adverse effects when EGFR-TKIs are used in combination with angiogenesis inhibitors than when used alone.ConclusionThe combination of EGFR-TKIs and angiogenesis inhibitors prolonged PFS in patients with EGFR-mutant advanced NSCLC, but the OS and ORR benefit was not significant, and the risk of adverse events was higher, more pronounced with hypertension and proteinuria; PFS in subgroups suggested that the combination was associated with better PFS in the smoking, liver metastasis, and no brain metastasis groups, and the included studies suggested that the smoking group , liver metastasis group, and brain metastasis group may have a potential OS benefit.

Immune phenotype-driven treatment outcome of IO-only versus chemo-IO in PD-L1-high, first-line, advanced non-small cell lung cancer (NSCLC).

e21179 Background: PD-L1 tumor proportion score (TPS) is the only biomarker for clinical decision-making regarding immunotherapy (IO) in advanced NSCLC. Currently, there is uncertainty when selecting treatment options between IO monotherapy (IO-only) and in combination with chemotherapy (Chemo-IO) when solely based on PD-L1, in patients with PD-L1 TPS ≥ 50%. Here, we explored a novel biomarker, immune phenotype as assessed by artificial intelligence (AI)-powered spatial tumor infiltrating lymphocytes (TIL) analysis to provide additional information in determining first-line treatment for advanced NSCLC, using a real-world dataset. Methods: A total of 349 whole-slide images (WSIs) of H&amp;E-stained slides for advanced/metastatic NSCLC patients without actionable EGFR mutation and ALK translocation treated with IO-only or Chemo-IO as their first-line were retrospectively collected from Samsung Medical Center. An AI-powered spatial TIL analyzer, Lunit SCOPE IO classified inflamed immune phenotype (IIP, the proportion of inflamed area ≥ 33.3% in tumor microenvironment) versus non-inflamed IP (non-IIP). PD-L1 TPS was assessed based on PD-L1 pharmDx 22C3 staining. Progression-free survival (PFS) was measured by the investigators per RECIST v1.1. Results: In the analysis set, all IO-only group (n = 84) had TPS ≥ 50%, but Chemo-IO group (n = 265) consisted of 21.1%, 29.8%, and 49.1% of TPS ≥ 50%, 1-49%, and &lt; 1%, respectively. Proportions of squamous cell carcinoma were not significantly different between IO-only and Chemo-IO (32.1% vs 27.5%, p = 0.5008). Proportions of IIP were significantly correlated with the TPS group, as they were 33.6%, 19.0%, and 13.1% in TPS ≥ 50%, 1-49%, and &lt; 1%, respectively (p = 0.0002). In the merged dataset (n = 349), PFS was significantly increased in IIP (22.6%) compared to non-IIP (median PFS [mPFS] 14.6 vs 6.0 m, 6-m PFS rate 72.1% vs 49.9%, hazard ratio [HR, 95% confidence interval] 0.57 [0.39-0.82], p = 0.0014). In TPS ≥ 50% group, IIP was significantly correlated with favorable PFS in IO-only group (IIP vs non-IIP; mPFS 14.6 vs 4.6 m, 6-m rate 65.5 vs 45.2%, HR 0.55 [0.31-0.98], p = 0.0375), however, it was not statistically different in Chemo-IO (n = 56, mPFS not reached [NR] vs 8.3 m, 6-m rate 88.5 vs 65.3%, HR 0.45 [0.15-1.33], p = 0.1185). Interestingly, in the subgroup of TPS ≥ 50% with IIP (n = 47), PFS was not significantly different based on treatment regimen (Chemo-IO vs IO-only, mPFS NR vs 14.6 m, 6-m rate 88.5 vs 65.5%, HR 0.52 [0.17-1.59], p = 0.2263), but Chemo-IO was significantly superior to IO-only in TPS ≥ 50% with non-IIP group (n = 93, mPFS 8.3 vs 4.6 m, 6-m rate 65.3 vs 45.2%, HR 0.53 [0.30-0.94], p = 0.0255). Conclusions: Immune Phenotype based on AI-powered spatial TIL analysis may provide complementary information for clinical decision-making between IO-only and Chemo-IO in advanced NSCLC patients with TPS ≥ 50%.

EE303 Cost-Effectiveness Analysis of Pd-L1 Testing Associated with Pembrolizumab for First-Line Treatment of Advanced NSCLC in China

To assess the cost-effectiveness of PD-L1 testing associated with Pembrolizumab for first-line treatment of advanced non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system.

Challenges of EGFR-TKIs in NSCLC and the potential role of herbs and active compounds: From mechanism to clinical practice.

Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of lung cancer, especially in the first-line treatment of advanced NSCLC, and EGFR-TKIs monotherapy has achieved better efficacy and tolerability compared with standard chemotherapy. However, acquired resistance to EGFR-TKIs and associated adverse events pose a significant obstacle to targeted lung cancer therapy. Therefore, there is an urgent need to seek effective interventions to overcome these limitations. Natural medicines have shown potential therapeutic advantages in reversing acquired resistance to EGFR-TKIs and reducing adverse events, bringing new options and directions for EGFR-TKIs combination therapy. In this paper, we systematically demonstrated the resistance mechanism of EGFR-TKIs, the clinical strategy of each generation of EGFR-TKIs in the synergistic treatment of NSCLC, the treatment-related adverse events of EGFR-TKIs, and the potential role of traditional Chinese medicine in overcoming the resistance and adverse reactions of EGFR-TKIs. Herbs and active compounds have the potential to act synergistically through multiple pathways and multiple mechanisms of overall regulation, combined with targeted therapy, and are expected to be an innovative model for NSCLC treatment.

Role of antiangiogenic agents in first-line treatment for advanced NSCLC in the era of immunotherapy

Background & objective“Anti-angiogenetic drugs plus chemotherapy” (anti-angio-chemo) and “immune checkpoint inhibitors plus chemotherapy” (ICI-chemo) are superior to traditional chemotherapy in the first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). However, in the absence of a direct comparison of ICI-chemo with anti-angio-chemo, the superior one between them has not been decided, and the benefit of adding anti-angiogenetic agents to ICI-chemo remains controversial. This study aimed to investigate the role of antiangiogenic agents for advanced NSCLC in the era of immunotherapy.MethodsEligible randomized controlled trials (RCTs) comparing chemotherapy versus therapeutic regimens involving ICIs or anti-angiogenetic drugs were included. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and rate of grade 3–4 toxicity assessment. R-4.3.1 was utilized to perform the analysis.ResultsA total of 54 studies with a sample size of 25,046 were finally enrolled. “Atezolizumab + Bevacizumab + Chemotherapy” significantly improved the ORR compared with “Atezolizumab + Chemotherapy” (Odds ratio (OR) = 2.73, 95% confidence interval (CI): 1.27–5.87). The trend also favored “Atezolizumab + Bevacizumab + Chemotherapy” in PFS and OS (hazard ratio (HR) = 0.71, 95% CI: 0.39–1.31; HR = 0.94, 95% CI: 0.77–1.16, respectively). In addition, “Pembrolizumab + Chemotherapy” and “Camrelizumab + Chemotherapy” significantly prolonged the PFS compared to “Bevacizumab + Chemotherapy” (HR = 0.65, 95% CI: 0.46–0.92; HR = 0.63, 95% CI: 0.41–0.97; respectively). Meanwhile, “Pembrolizumab + Chemotherapy” and “Sintilimab + Chemotherapy” yielded more OS benefits than “Bevacizumab + Chemotherapy” (HR = 0.69, 95% CI: 0.56–0.83; HR = 0.64, 95%CI: 0.46–0.91; respectively). Scheme between “Atezolizumab + Bevacizumab + Chemotherapy” and “Atezolizumab + Chemotherapy” made no significant difference (OR = 1.18, 95%CI: 0.56–2.42) concerning the rate of grade 3–4 toxicity. It seemed that ICI-chemo yielded more improvement in quality-adjusted life-year (QALY) than “Bevacizumab + Chemotherapy” in cost-effectiveness analysis.ConclusionOur results suggest that ICI-chemo is associated with potentially longer survival, better cost-effectiveness outcomes, and comparable safety profiles than anti-angio-chemo. Also, adding bevacizumab to ICI-chemo seemed to provide additional therapeutic benefits without adding treatment burden. Our findings would supplement the current standard of care and help the design of future clinical trials for the first-line treatment of patients with advanced NSCLC.

Efficacy and safety of immune checkpoint inhibitors combined with recombinant human endostatin and chemotherapy as the first-line treatment of advanced non-small-cell lung cancer.

Aim: To assess the efficacy and safety of combination of PD-1 inhibitors, recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Methods: A total of 100 patients with advanced NSCLC were retrospectively reviewed and analyzed (58 in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy; 42 in the group receiving Rh-endostatin and chemotherapy). The primary end point was progression-free survival. Results: Patients in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy had significantly improved progression-free survival (10.2 vs 6.5months; p<0.001) and objective response rate (67.2 vs 42.9%; p=0.015), with acceptable toxicity. Conclusion: Our study showed the superiority of combination therapy of PD-1 inhibitors and Rh-endostatin as first-line treatment for advanced NSCLC.

The Real-world Therapeutic Analysis of First-line Immunotherapy in Chinese Patients with Drive Gene Positive for Advanced Non-Small Cell Lung Cancer.

Background: Immune checkpoint inhibitors (ICIs) are widely used for treating advanced non-small cell lung cancer (NSCLC). However, some studies indicate that patients with genetic mutations do not benefit from immunotherapy. Hence, this study explored the efficacy of anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) antibodies in the first-line treatment of advanced NSCLC with driver gene mutations in real-world settings. Methods: We retrospective analyzed patients with advanced NSCLC who treated with first-line anti-PD-1/PD-L1 antibodies at Shandong Provincial Hospital between May 2019 and October 2020. The patient's driver gene mutation status was identified using amplification refractory mutation system PCR (ARMS-PCR). The basic clinical characteristics, objective response rate (ORR), progression free survival (PFS), and other clinical data of patients were collected to evaluate the clinical efficacy and potential prognostic factors of treatment for patients with driver gene mutations. Results: A total of 430 patients' information was counted during this period, finally, 89 patients with NSCLC were enrolled in the study. The main pathological subtype of patients was adenocarcinoma (62.9%). The overall mutation rate was 44.9% (n = 40) and included following mutations: KRAS (n = 20), TP53 (n = 18), EGFR (n = 6), BRAF (n = 3), Her-2 (n = 3), MET (n = 3), ROS1 (n = 1), and NRAS (n = 1). The overall ORR was 44.30% and the disease control rate (DCR) was 82.23%. At the time of follow-up cut-off, the median PFS of all patients was 8.2 month. In NSCLC patients treated with ICI, median PFS was longer in mutation-negative patients than in mutation-positive patients (8.98 vs 7.07 months, P < 0.05). Survival benefit varied across mutational subgroups: KRAS patients could benefit from first-line immunotherapy (10.1 months, P < 0.05), patients with EGFR mutations have poor first-line immunotherapy outcomes, with a median PFS of only 3.0 months (P < 0.01), and patients with other mutation types having no significant difference in response from mutation-negative patients. In most mutation subgroups, immune combination therapy had longer PFS than immune monotherapy, and PD-L1 expression levels were positively correlated with clinical benefit in patients. Conclusion: In the real world, patients with KRAS mutations benefit from first-line immunotherapy, immune-combination modalities are more effective, and immune efficacy is positively correlated with PD-L1 expression; Patients with other driver mutations (BRAF, NRAS, Her2, MET, ROS1) benefit similarly to mutation-negative patients in first-line immunotherapy, and immunotherapy is recommended for first-line therapy; Immunotherapy is worse effective in patients with EGFR mutations, immunotherapy is not recommended in first-line therapy even patients with high PD-L1 expression.

Cost-effectiveness of nivolumab plus ipilimumab versus chemotherapy as first-line therapy in advanced non-small cell lung cancer.

First-line treatment with nivolumab plus ipilimumab has been shown to improve overall survival (OS) and progression-free survival (PFS) for patients with advanced non-small cell lung cancer (NSCLC). The current study evaluated the cost-effectiveness of nivolumab plus ipilimumab versus chemotherapy in advanced NSCLC from the perspective of Chinese healthcare system. A three state-transition Markov model was employed to evaluate the cost and effectiveness of nivolumab plus ipilimumab versus chemotherapy in the first-line treatment of advanced NSCLC. Key clinical data in the model were derived from Part 1 of the phase 3 CheckMate 227 trial (NCT02477826). Costs and utilities were obtained from published literatures. The main endpoints of the model were costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. Nivolumab plus ipilimumab was associated with an increase in overall cost of $95,867.82 and improved effectiveness of 0.98 QALYs compared with chemotherapy, yielding an ICER of $97,676.24 per QALY. In one-way sensitivity analysis, the variables that had the greatest influence on the ICER were hazard ratio for OS and body weight. In probabilistic analysis, nivolumab plus ipilimumab had a 0% probability of being cost-effective at a willingness-to-pay (WTP) threshold of $37,663.26/QALY in China. However, the combination therapy would become cost-effective when the cost of nivolumab and ipilimumab were discounted by 65%. First-line nivolumab plus ipilimumab treatment for advanced NSCLC was found to be not cost-effective compared with chemotherapy at a WTP threshold of $37,663.26/QALY in China.

1042P Efficacy and safety of immune checkpoint inhibitors combined with recombinant human endostatin first-line therapy for advanced non-small cell lung cancer

Clinical evidences of Immune checkpoint inhibitors (ICIs) plus antiangiogenic drugs as the first-line therapy for advanced non–small-cell lung cancer (NSCLC) were still insufficient, which greatly limited the application of evidence-based medicine in clinic. This study aimed to investigate the efficacy and safety of PD-1 inhibitors in combination with recombinant human endostatin (Rh-endostatin) and chemotherapy as the first-line treatment for advanced NSCLC. Clinical data of 100 patients with NSCLC were retrospectively analyzed. Among them, 58 patients in the experimental group (IEC group) were treated with PD-1 inhibitors combined with Rh-endostatin and chemotherapy, and 42 patients treated with Rh-endostatin and chemotherapy were in the control group (EC group). The primary end point was progression-free survival (PFS), secondary end points included the objective response rate (ORR), disease control rate (DCR), and adverse events were compared between the IEC group and EC group. The IEC group showed significantly improved ORR (67.2% vs 42.9%, P = 0.015) and prolonged PFS (10.2 months vs 6.5 months, P < 0.001). The DCR and 1-year OS rate in the IEC group was higher than that in the EC group, while the difference was not statistically significant (98.3% vs 90.5%, P=0.193; 79.3% vs 76.2%, P=0.710). Cox multivariate regression analysis revealed that treatment modality, brain metastasis and clinical stage might be independent risk factors for median PFS (mPFS). There were no significant differences in adverse events between two groups. Our study showed the superiority of combination therapy of PD-1 inhibitors combined with Rh-endostatin as first-line treatment for advanced NSCLC in terms of ORR and PFS, which represented a promising treatment modality for this population.

EP08.02-022 Investigating Partners in Crime: Osimertinib Resistance Mechanisms in Non-small Cell Lung Cancer Using Focused CRISPR Screen

Non-small cell lung cancer (NSCLC) is the most prevalent and detrimental cancer type, accounting for 85% of all lung cancer cases. EGFR mutations, which can be targeted by tyrosine kinase inhibitors (TKIs), have been addressed as one of the cancer driving mechanisms in NSCLC adenocarcinomas. Osimertinib, a third generation EGFR-TKI, has been recently approved for clinical use in the first-line treatment of advanced NSCLC. Unfortunately, the long-standing obstacle in EGFR-TKI treatments, including Osimertinib, is the inevitable resistance.