Platinum-based Doublet Research Articles

Role of Thoracic Radiotherapy in Extensive Stage Small Cell Lung Cancer (ES-SCLC) in the Immunotherapy Era: A National Hospital-Based Registry Analysis

Immunotherapy has shaped the treatment for a number of metastatic cancer types. Based on IMPower 133 and CASPIAN results, chemoimmunotherapy has become standard of care for de-novo ES-SCLC, with increase in median survival of approximately 2-3 months compared to prior standard of care platinum-based doublet therapy with etoposide. However, neither of these trials allowed consolidative thoracic radiotherapy (TRT). Prior to chemo-immunotherapy trials, addition of consolidative TRT to standard chemotherapy improved 2 years survival in patients with any response to chemotherapy. At present, there is no prospective data of role of TRT in ES-SCLC with chemoimmunotherapy. We undertook this study to examine any benefit of TRT in patients with ES-SCLC who received chemoimmunotherapy.We queried the National Cancer Database (NCDB) for patients with ES-SCLC between the ages of 18-90 years treated between 2012-2017 treated with combination of chemotherapy and immunotherapy at the time of diagnosis, and with and without TRT. We excluded patients with unknown treatment status or follow-up time. Overall survival was estimated using Kaplan-Meier method and compared between treatment groups utilizing log-rank testing. An optimal-full propensity-score match was performed utilizing clinical and demographic covariates to reduce the impact of potential confounders of overall survival on the probability of receipt of TRT. Cox proportional hazards regression was used to identify predictors of overall survival.A total of 244 patients were identified meeting selection criteria, treated between 2012 and 2016. There were 63 patients that received TRT and 181 patients that did not. The median age was 65 (40-90) years. The median follow-up was 9.68 (range 0.7-48.3) months. After propensity score matching by age, gender, race, comorbidity score, and type of chemotherapy, there was a trend towards improved median survival from 9 to 11 months and 2 year OS at 18.1% with the addition of TRT vs 12.0% with chemoimmunotherapy alone (P = 0.067). On multivariable analysis only female gender was significantly associated with improved OS after adjustment for age, race, comorbidity score, gender, and receipt of TRT (HR = 0.67 (95% CI 0.51 - 0.89), P = 0.01).In patients with ES-SCLC, the addition of TRT to chemoimmunotherapy is associated with a trend towards improved median and 2 year OS on the order of magnitude of the addition of immunotherapy to chemotherapy as reported in recent trials, though this was not statistically significant in the context of a limited sample size from a non-randomized cohort. Data from prospective, randomized trials are needed to help identify which patients may benefit from TRT in the immunotherapy era.

1183P Survival impact of concurrent chemoradiotherapy (CRT) with weekly cisplatin doses in patients with unresectable stage III non-small cell lung cancer (NSCLC) in a clinical referral center in Chile

In Chile, lung cancer is the second leading cause of cancer-related death. Most diagnoses are made in an advanced stage, with one third of all NSCLC cases in stage III unresectable disease, with a 5-year OS of 15%. The current standard of care for these patients has been platinum-based doublets with concurrent radiation therapy in combination with immunotherapy (IO).

812P Demographics and survival outcomes in patients with advanced or recurrent endometrial cancer (EC) following platinum-based doublet (PBD) in the English real-world (RW) setting

Patients with advanced/recurrent EC following disease progression on or after a PBD therapy have a poor prognosis. This descriptive, noninterventional, retrospective cohort study reports on English patient characteristics and survival outcomes, specifically in a population with advanced/recurrent EC that has progressed on or after a first-line (1L) PBD therapy.

Algorithme thérapeutique des CBNPC sans anomalie moléculaire actionnable: Therapeutic algorithm for NSCLC without actionable molecular abnormalities

The development of immunotherapy in first-line therapy with anti-PD-1 and anti-PD-L1 has changed the first line treatment algorithm of advanced NSCLC. The anti-PD-1 pembrolizumab and cemiplimab clearly improve the overall survival in NSCLC with high PD-L1 expression (≥ 50% of tumour cells), comparatively to cytotoxic chemotherapy. Combinations of anti-PD(L)-1 to platinum-based chemotherapy are superior to chemotherapy alone, independently of PD-L1 level of expression. They represent the 1st line gold-standard when PD-L1 is expressed in less than 50% of tumour cells and might reduce the risk of early disease progression in comparison with pembrolizumab when PD-L1 ≥50%. The room for anti-CTLA-4 + anti-PD(L)-1 combinations which are not available in France remains to be established. Second-line treatment is currently based on chemotherapy, with a platinum-based doublet for patients treated in first line by pembrolizumab alone, and standard second-line chemotherapy options for patients treated by chemotherapy-immunotherapy combinations, i.e. docétaxel regardless of histology or pemetrexed for non-squamous cell carcinoma when not used in first line. Addition of an antiangiogenic agent to docetaxel only achieved a modest improvement of overall survival but neither nintedanib nor ramucirumab are available in France. Immunotherapy still benefits only a minority of patients whose identification is imperfect, underscoring the need for new strategies based on characterizing, initiating, and amplifying the anti-tumour immune response as well as understanding the mechanisms of resistance to treatment in order to improve these results.© 2021 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Perioperative Therapy for Non-Small Cell Lung Cancer with Immune Checkpoint Inhibitors.

Simple SummaryThis review presents the development of perioperative treatment using immune checkpoint inhibitors (ICIs) in patients with resectable non-small cell lung cancers. There are several ongoing phase 3 trials for adjuvant and neoadjuvant ICI therapies. The results of the adjuvant (IMpower010 trial) and the neoadjuvant (Checkmate 816 trial) ICI phase 3 trials have shown prolonged disease-free survival and increased pathological complete response rate, respectively. Based on the hypothesis that ‘preoperative ICI treatment, especially in combination with conventional chemotherapy, promotes a higher immune response because of preservation of the immune environment’, neoadjuvant trials using ICIs and conventional chemotherapy in combination are currently being conducted more frequently than adjuvant ICI trials. Multimodality approaches using chemoradiotherapy and new ICI agents are also being examined in several phase 2 trials. To maximise ICI therapy’s efficacy and to minimise futile administration, methodologies for predicting and monitoring the therapeutic effects, such as detecting minimal residual disease, need to be established.The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment landscape for patients with metastatic non-small cell lung cancer (NSCLC). These achievements inspired investigators and pharmaceutical companies to conduct clinical trials in patients with early-stage NSCLC because both adjuvant and neoadjuvant platinum-based doublet chemotherapies (PT-DCs) showed only a 5% improvement in 5-year overall survival. IMpower010, a phase 3 trial (P3), showed that adjuvant PT-DC followed by maintenance atezolitumab significantly prolonged disease-free survival over adjuvant PT-DC alone (hazard ratio, 0.79; stage II to IIIA). Since conventional therapies, including chemotherapy and radiotherapy, can promote immunogenic cell death, releasing tumour antigens from dead tumour cells, ICI combination therapies with conventional therapies are widely proposed. The Checkmate 816 trial (P3) indicated a significantly higher pathological complete response rate of neoadjuvant nivolumab/PT-DC combination therapy than of neoadjuvant PT-DC alone (odds ratio, 13.9, for stage IB to IIIA). Detection of circulating tumour DNA is highly anticipated for the evaluation of minimal residual disease. Multimodal approaches and new ICI agents are being attempted to improve the efficacy of ICI treatment in phase 2 trials. This review presents the development of perioperative treatment using ICIs in patients with NSCLC while discussing problems and perspectives.

The impact of the SARS-COV2 pandemic on the delivery of chemotherapy for gynecologic cancer at a tertiary care institution in the United States epicenter

Objectives:In New York City, the SARS-CoV2 pandemic epicenter of the United States, the surge of cases predated much of the country by several weeks, leading to changes in practice patterns that have informed decisions made by other medical institutions. As the SARS-CoV2 pandemic unfolded, many professional subspecialty organizations released practice guidelines in order to minimize transmission of COVID-19 and protect vulnerable populations. The impact of modifications to traditional gynecologic cancer treatment is not known. Here, we describe the impact of the SARS-COV2 pandemic on chemotherapy practices for gynecologic cancer during the pandemic surge.Methods:We identified patients age 18 or older at Montefiore Medical Center who had a confirmed or suspected diagnosis of gynecologic cancer and received care between March 16, 2020 and June 7, 2020; these dates reflect a series of executive orders issued by the Governor of New York allowing the State Commissioner of Health to cancel elective procedures at hospitals and ambulatory surgery centers. Clinical data were abstracted from patients’ charts. Patients with incomplete treatment records were excluded.Results:A total of 146 women who were included to whom 169 cycles of cytotoxic chemotherapy were delivered during the study period and 68 women (46.6%) received at least one cycle of chemotherapy. Nine patients screened positive for symptoms of COVID or active infection during the study period. Among patients receiving chemotherapy, 52.9% (n=36) had modifications to traditional cancer treatment as a result of state and institutional regulations. Dose reduction was the leading pandemic-related treatment modification and occurred in 69.4% of patients (n=25). Other treatment modifications included prophylactic use of pegfilgrastim (n=1), and treatment deferral or delay (n=7). Women receiving a platinum-based doublet (n=36) during the study period were more likely to sustain dose reduction in chemotherapy (25%) compared to patients undergoing other regimens (0%). A total of 111 women received at least one dose of disease-modifying therapy during the cohort period including chemotherapy, immunotherapy, anti-angiogenesis agents, hormonal therapy, PARP inhibitors, or investigational agents. Treatments were most often discontinued due to completion of adjuvant therapy (n=5), progression of disease (n=4), or toxicity (n=5). Notably 5 patients chose to defer therapy in the setting of the pandemic surge. Only one patient was identified as receiving neoadjuvant chemotherapy specifically due to COVID pandemic-related restrictions.Conclusions:The SARS-COV2 pandemic has led to modification of current standard chemotherapy delivery for gynecologic malignancies with the shared goal of protecting the most vulnerable populations from COVID infection. The impact of these modifications on cancer specific outcomes is not yet known. Future investigation will focus on identifying whether treatment modification to circumvent iatrogenic immunosuppression compromises oncologic outcomes.

Surgery alone, adjuvant tegafur/gimeracil/octeracil (S-1), or platinum-based chemotherapies for resectable gastric cancer: real-world experience and a propensity score matching analysis

BackgroundAdjuvant chemotherapy has changed the paradigm in resectable gastric cancer. S-1 is an oral chemotherapeutic with promising efficacy in Asia. However, comparisons with close observation or platinum-based doublets post D2 gastrectomy have been less reported, notably on real-world experiences.MethodsWe retrospectively evaluated patients with D2-dissected stage IB-III gastric cancer who received S-1 (S-1, n = 67), platinum-based doublets (P, n = 145) and surgery with close observation (OBS, n = 221) from Jan 2008 to Oct 2018. A propensity score matching was used to compare for recurrence-free (RFS) and overall survivals (OS) in patients who had a locally-advanced disease (T3–4 or lymph node-positive). Adverse reactions, dosage, and associated factors for S-1 are also discussed.ResultsIn a median follow-up time of 51.9 months, adjuvant S-1 monotherapy was associated with an intermediate survival as compared with P and OBS (median RFS/OS: S-1 vs. P, 20.9/35.8 vs. 31.2/50.5 months, HR = 1.76/2.14, p = 0.021/0.008; S-1 vs. OBS, 24.4/40.2 vs. 20.7/27.0 months, HR = 0.62/0.55, p = 0.041/0.024). The survival differences were more prominent in patients with N2–3 diseases. S-1 was well-tolerated with a relative dose intensity of 73.6%, a median duration of 8.3 months and associated with less adverse reactions as compared with P. S-1 monotherapy was selected by physicians based on age, lymph node stage, serum carcinoembryonic antigen and disease stage.ConclusionsAdjuvant S-1 correlated with intermediate survival outcomes between OBS and P but conferred fewer adverse reactions as compared with P. Patients with a moderate risk of recurrence had comparable survivals when treated with S-1 while platinum-based doublets were favored in advanced cases. The study provides additional information about adjuvant S-1 in patients with selected risk of recurrence.

Abstract CT041: ORIENT-3: A randomized, open-label, phase 3 study of sintilimab versus docetaxel in previously treated advanced/metastatic squamous non-small-cell lung cancer (sqNSCLC)

Abstract Background: Patients (pts) with advanced squamous NSCLC (sqNSCLC) have very limited second-line treatment options after failure of the platinum-based doublet chemotherapy. ORIENT-3 was conducted to compare the efficacy and safety of sintilimab, an anti-PD-1 antibody, with docetaxel in second-line treatment in sqNSCLC. (NCT03150875) Method: Pts with stage IIIB/IIIC or IV (ineligible for radical chemo-radiotherapy) sqNSCLC who have disease progression during or after first-line platimum-based chemotherapy were enrolled and randomized 1:1 to receive sintilimab 200mg (Sin arm) or docetaxel 75mg/m2 (Doc arm) intravenously, Q3W until disease progression or intolerable toxicity. Stratification factor was ECOG score (0 vs. 1). The primary endpoint was overall survival (OS). Results: As of July 31, 2020, 290 pts were enrolled with 145 in each treatment group. Efficacy analysis was based on FAS (n=280), and safety analysis was based on safety set (n=274). Baseline characteristics were well balanced between treatment groups, and most pts in efficacy analysis (75.9% in Sin arm, 77.0% in Doc arm) had ECOG PS score of 1. Pts received a median of 8.0 cycles (range: 1-45) of sintilimab, and 2.0 cycles of docetaxel (range: 1-15). With a median follow-up of 23.56 months, sintilimab had a significant improvement in OS versus docetaxel (median: 11.79 m [95% CI 10.28-15.57] vs. 8.25 m [95% CI 6.47-9.82]; HR 0.74, [95%CI 0.56-0.96], P = 0.02489). The median PFS was also significantly superior in Sin arm (4.30 m, 95% CI 4.04-5.78) to that in Doc arm (2.79 m, 95% CI 1.91-3.19) (HR 0.52, 95% CI 0.39-0.68, P<0.00001). The confirmed ORR was 25.5% (95% CI, 18.6%-33.4%) in Sin arm and 2.2% (95% CI 0.5%-6.4%) in Doc arm. 84.7% of pts in Sin arm and 83.1% in Doc arm reported treatment-related adverse events (TRAEs), most commonly with hypothyroidism (18.1%) and alopecia (34.6%), respectively. TRAEs ≥ grade 3 were less frequent in Sin arm (18.1%) than in Doc arm (36.2%). Five pts occurred sintilimab-related death, and one death reported relating with docetaxel. Conclusion: Sintilimab as second-line treatment for advanced and metastatic sqNSCLC showed a superior OS and PFS benefit, compared with docetaxel. Citation Format: Yuankai Shi, Lin Wu, Xinmin Yu, Yan Wang, Puyuan Xing, Jianying Zhou, Airong Wang, Jianhua Shi, Yi Hu, Ziping Wang, Guangyu An, Yong Fang, Sanyuan Sun, Caicun Zhou, Changli Wang, Feng Ye, Xingya Li, Junye Wang, Mengzhao Wang, Yunpeng Liu, Yanqiu Zhao, Jifeng Feng. ORIENT-3: A randomized, open-label, phase 3 study of sintilimab versus docetaxel in previously treated advanced/metastatic squamous non-small-cell lung cancer (sqNSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT041.

PCN41 Enhanced Cost-Effectiveness Analysis Using EHR Data for Real World Value

Real-world evidence (RWE) generated from electronic health records (EHR) has been shown to be more relevant, timely, and representative for health technology assessment decision-making compared to evidence from clinical trials. We assessed how using EHR-derived RWE instead of published clinical trial data can impact point estimates and uncertainty ranges in cost-effectiveness estimates for advanced non-small cell lung cancer (NSCLC) therapies. We replicated a cost-effectiveness analysis of NSCLC therapies developed by the Institute for Clinical and Economic Review in 2016 (“traditional”), replacing meta-analysis-derived hazard ratios from clinical trials with RWE-derived hazard ratios for progression-free and overall survival (“RWE-enhanced”). Hazard ratios were calculated using Cox proportional hazards models adjusted for age, sex, race, practice type, performance status, and smoking history. The study used the Flatiron Health database, a nationwide (US-based) longitudinal, de-identified EHR-derived database. We compared the cost-effectiveness of immunotherapy (atezolizumab, pembrolizumab, nivolumab) vs. chemotherapy (single-agent docetaxel) in the second line of therapy. The analytic cohort included 3,492 adults with EGFR- NSCLC that progressed after first-line treatment with a platinum-based chemotherapy doublet. We report traditional and RWE-enhanced incremental cost-effectiveness ratios (ICERs) and differences in uncertainty as percent change in the size of 95% credible intervals (CIs). The traditional vs RWE-enhanced ICERs were as follows: atezolizumab — $84,000/quality-adjusted life year (QALY) vs. $138,000/QALY; nivolumab — $136,000/QALY vs. $123,000/QALY; pembrolizumab — $181,000/QALY vs $111,000/QALY. Compared to uncertainty in traditional ICERs, 95% CIs for RWE-enhanced ICERs were reduced by 37%, 69%, and 83% for atezolizumab, nivolumab, and pembrolizumab respectively. This proof-of-concept demonstrated how clinical depth, longer follow-up time, and larger sample sizes in EHR-derived data may reduce uncertainty in cost-effectiveness analysis. The approach has potential to inform dynamic value-based pricing and highlights the importance of reassessments once RWE is available.

CE3 Systematic Review and Indirect Comparison of PD-(L)1 Inhibitors in Combination with Platinum-Based Doublet Chemotherapy (PT-DC) for the First-Line Treatment of Non-Squamous, Non-Small-Cell Lung Cancer (nsqNSCLC)

CE3 Systematic Review and Indirect Comparison of PD-(L)1 Inhibitors in Combination with Platinum-Based Doublet Chemotherapy (PT-DC) for the First-Line Treatment of Non-Squamous, Non-Small-Cell Lung Cancer (nsqNSCLC)

A phase 1b, open-label, single-arm study of cofetuzumab pelidotin (a PTK7-targeting antibody-drug conjugate) in patients with PTK7-expressing, recurrent non-small cell lung cancer (NSCLC).

TPS3142 Background: Protein tyrosine kinase 7 (PTK7) is a highly conserved receptor tyrosine kinase involved in the Wnt signaling pathway and is overexpressed in multiple cancer types, including non-small cell lung cancer (NSCLC). Cofetuzumab pelidotin (ABBV-647) is an anti-PTK7 antibody-drug conjugate comprising the hu6MO24 monoclonal antibody, a cleavable cysteine-reactive linker, and Aur0101 (an auristatin microtubule inhibitor). It has shown promising preclinical anti-tumor effects (Damelin et al. Sci Transl Med 2017;9[372]:eaag2611) and clinical activity with a manageable safety profile in a Phase 1 study in patients with advanced solid tumors, with promising anti-tumor activity noted in NSCLC (Sachdev et al. DOI: 10.1200/JCO.2018.36.15_suppl.5565). Methods: This open-label, single-arm, multicenter Phase 1b study (NCT04189614) will assess the anti-tumor activity and safety of cofetuzumab pelidotin in approximately 40 patients with PTK7-expressing, recurrent NSCLC. The primary objective is to assess the objective response rate of cofetuzumab pelidotin according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary objectives include the duration of response, progression-free survival, overall survival, and safety and tolerability. Pharmacokinetic and biomarker samples will also be collected throughout for analysis. Patients must be aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0–1 and have recurrent histologically confirmed NSCLC with PTK7-expressing tumor (using a validated immunohistochemistry assay). Patients must have progressed after treatment with a platinum-based chemotherapy doublet and an immune checkpoint inhibitor (for tumors without targetable genetic alterations), or a platinum-based chemotherapy doublet and targeted agent(s) (for tumors with targetable genetic alterations). Patients must also have received ≤2 prior lines of systemic therapy (≤3 prior lines for tumors treated with targeted agent[s] for genetic alterations), including no more than 1 line of systemic chemotherapy. Cofetuzumab pelidotin (2.8 mg/kg) is administered intravenously every 3 weeks until the patient experiences disease progression, intolerable toxicity, or other study treatment discontinuation criteria are met. The study commenced on February 13, 2020 and enrollment is ongoing. Clinical trial information: NCT04189614.

Concurrent chemoradiotherapy with weekly cisplatin in stage III unresectable non-small cell lung cancer (NSCLC): A local experience with LATAM patients.

e20535 Background: Lung cancer is the leading cause of cancer related death worldwide and so is expected in Chile in 2021 accoding to Globocan, with a 12.4% mortality rate last year. Among NSCLC, 35 to 40% present as locally advanced disease, most of them non surgical candidates. Current standard of treatment is platinum-based doublet with concurrent Radiotherapy plus adyuvant durvalumab since 2018. Still many controversies related to different approaches are not settled. Few literature is available concerning a less aggressive approach in order to achieve a more tolerable treatment for the patient preserving effectiveness. Many patients compromise the treatment compliance due to early toxicities. We present our preliminary results of local data consisting in weekly cisplatin plus concurrent standard dose of radiotherapy. Methods: We performed a retrospective review of local database for stage III unresectable NSCLC between 2013 to 2019. Baseline clinical data , treatment modality, toxicities and response rates were recorded for all patients. Outcomes were analyzed by measuring overall response rate (ORR) , progression free (PFS) and overall survival (OS). Toxicities were assessed by CTCAE v5.0 and treatment response by RECIST 1.1 criteria. Results: 54% of the patients were men, 68%ECOG 0 and 32% ECOG 1. Mean BMI of 26 kg / m2. 100% smokers with average 39 packages per year and 71% had some other comorbidity;. 26% had emphysema. Histologic confirmation of 74%adenocarcinom and as. 26% squamous cell carcinoma. Staging analysis showed 23% stage IIIA, 54% stage IIIB, and 23% stage IIIC. Only 6 patients received adjuvant treatment before being diagnosed with stage III disease. Chemoradiotherapy is carried out as follows: 86% cisplatin (median 54.4 mg/m2) as a single weekly dose combined with standard radiotherapy of 60 Gy /30 Fr in a concurrent modality in ???. 74.2% completed follow up after CRT and the remaining 50% received adyuvant durvalumab. 71% of the patients reported some degree (mild, moderate or severe?) of toxicity related to the treatment; 37.1% grade 2 actinic pneumonitis, 11.4% grade 2 actinic esophagitis and 11.4% grade 1 acute renal failure among the most significant. No CTCAE 5.0 grade 4 and 5 toxicities were reported. 82.8% progressed in 15 months average (mean??); with 17% with current stable disease. The ORR was 48,5%. The mOS was 23 months (95% CI [16,7-29,3]) and the mPFS was 10 months (95% CI [8.25-11.75]. Conclusions: Since PACIFIC trial, stage III unresectable NSCLC have experienced a pivotal change in management. Unfortunately, our Public Health Insurance System does not cover access for all pts. This approach reaches similar results described in earlier trials published in the area and could be an option in certain clinical settings.

Analysis of first-line treatment (tx) patterns in advanced non-small cell lung cancer (NSCLC) patients (pts) with compromised performance status (PS), organ dysfunction (dfxn) or other significant comorbidities.

e21093 Background: NSCLC is a disease of the elderly and most cases are related to tobacco. Therefore, concomitant organ dfxn, which increases the risk of toxicity with cancer directed therapy, is prevalent. Patterns of care studies have shown that the elderly, those with organ dfxn or compromised PS are frequently not treated, despite prospective studies demonstrating survival benefit with active tx. We hypothesized that the advent of new, more active therapies has resulted in practice changes in these populations. Methods: We conducted a retrospective, observational cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to compare first line tx patterns from 2011 to 2020 in pts with advanced NSCLC meeting at least 1 of the following criteria: age > 70 years, organ dfxn (serum creatinine > 1.5 times the upper limit of normal [ULN] and/or total bilirubin > 2 times ULN), ECOG PS > 2 or documented HIV. Pts were excluded if there was a > 90-day post-diagnosis gap in EHR data. Tx patterns were categorized as having received standard, non-standard or no frontline tx. Tx groups included PD-1/PD-L1 inhibitor single agent, chemoimmunotherapy, platinum-based (Plat) doublet +/- VEGF inhibitors (VEGFi), single agent chemotherapy (chemo) and tyrosine kinase inhibitors (TKIs). Descriptive statistics were used to analyze tx patterns, and the relationship between txs and variables of interest were tested using Chi-squared tests or t-tests. Results: Of the 58,145 pts with advanced NSCLC in the database, 33,701 met at least 1 criterion for inclusion. There was a small but significant increase in the number of pts treated with standard therapy from 2011 to 2020 (p < 0.001). There was rapid uptake of PD-1/PD-L1 inhibitors as well as chemoimmunotherapy upon FDA approvals in 2016 and 2018, respectively. This correlated with a rapid decrease in the use of Plat-doublet chemo +/- VEGFi as well as a decrease in the number of pts receiving single agent chemo or not treated at all (Table). Conclusions: Real world data from 2011 to 2020 demonstrates an increase in the use of standard therapies as well as the rapid incorporation of immunotherapy into first line tx in advanced NSCLC pts who are elderly, have a poor PS, or organ dfxn. However, a substantial proportion of pts (28.9%) still do not receive any documented tx, within the Flatiron Health network.[Table: see text]

Optimizing the program of sequential chemotherapy for advanced gastric cancer based on gene-level CNVs called from ctDNA.

e16068 Background: Tumor evolutionary trade-offs under treatment pressure can be utilized to optimize therapy. We aimed to profile the dynamic pattern of gene-level copy number variations (CNVs) for advance gastric cancer (GCA) patients who underwent sequential chemotherapy and optimized the therapy program. Methods: 27 chemo-naive advanced GCA patients with distant metastasis were enrolled. Peripheral blood samples were collected at different time points, including pre-therapy and disease progression on a specific regimen. Gene-level CNVs were called from ctDNA of blood samples and drug modified score (DMS) was defined as the ratio of CNV value between samples of pre- and post-treatment for each gene. Positive and negative DMS of a gene represented its resistance and sensitivity to a selected regimen, respectively. Then, the best initial regimen was selected and the optimal program of sequential chemotherapy was designed for each patient. Results: DMS of gene was calculated for four chemotherapy regimens, including platinum-based doublet regimen (Pt-2d), oral-fluorouracil prodrug (O-FP), paclitaxel-based regimen (PTX) and irinotecan-based regimen (CPT-11). Based on DMS distribution, resistant and sensitive genes were determined for each regimen through a heuristic method. Functional enrichment analysis showed that resistant genes mainly involved in cellular response to oxygen-containing compound and regulation of cell proliferation, while sensitive genes mainly involved in positive regulation of macromolecule biosynthetic process and regulation of apoptotic process. Then, drug resistant score (DRS, defined as DMS weighted sum of CNV values of resistant genes) was calculated and the regimen with the lowest DRS was selected as the best initial treatment for each patient. The best initial treatment of 16 patients was CPT-11, of 8 patients was O-FP, of 2 patients was Pt-2d and of 1 patient was PTX. Following that, the optimal program of sequential chemotherapy was designed according to the percentage of shared resistant genes between regimens for each patient, where two regimens with the lowest percentage were recommended to use one by one. Finally, prognostic analysis showed that differences between the optimal and practical program of sequential chemotherapy were negatively correlated to overall survival of patients. Conclusions: Based on gene-level CNVs called from ctDNA of blood samples, we determined the best initial treatment and designed the optimal program of sequential chemotherapy for advanced GCA patients, pacing a key step toward precision medicine in GCA field.

Phase II trial of toripalimab plus chemotherapy as neoadjuvant treatment in resectable stage III non-small cell lung cancer (NeoTPD01 Study).

8541 Background: Multi-modality treatment provides modest survival benefits for locally advanced non-small-cell lung cancer (NSCLC) patients. Preoperative immunotherapy has continuously been shown to be promising in treating resectable NSCLC. The current study aimed to investigate the activity and safety of the PD-1 inhibitor, toripalimab, with chemotherapy given as neoadjuvant treatment for resectable stage III NSCLC in Asian population. Methods: Eligible patients recruited were aged 18 years or older with histologically confirmed AJCC-defined stage IIIA or T3-4N2 IIIB NSCLC who deemed surgically resectable. Patients received 3 cycles of neoadjuvant treatment with intravenous toripalimab (240 mg), carboplatin (area under curve 5), and pemetrexed (500 mg/m2 for adenocarcinoma) or nab-paclitaxel (260 mg/m2 for others) on day 1 of each 21-day cycle. Surgical resection was performed 4-5 weeks following the first day of the last cycle of treatment. The primary endpoint was major pathological response (MPR; ≤10% viable tumor cells). Secondary endpoints included pathological complete response (pCR), R0 resection rate, disease-free survival and safety. Paired primary tumor +/- lymph node and blood samples at baseline and surgery were obtained for exploratory study. This study is registered with ClinicalTrials.gov, NCT04304248. Results: Between August 2019 and July 2020, 33 patients (median age: 61, IQR: 56-66; female: 6, 18.2%) were enrolled and received neoadjuvant treatment. 18 (54.5%) patients had squamous cell lung cancer, and 13 (39.4%) had T3-4N2 stage IIIB disease. Two patients refused surgery and one had progressive disease after treatment. 30 (91.9%) patients underwent resection (median interval between neoadjuvant treatment and surgery: 36.5 days, IQR 30-42.5) and all except one achieved R0 resection (29/30, 96.7%). 20 patients (20/30, 66.7%) had an MPR, including 15 patients (15/30, 50.0%) had a pCR in the per-protocol population. Surgical complications included three arrhythmias, one prolonged air leak, and one chylothorax. 24 patients (80.0%) had pathological downstaging following treatment, and complete lymph node clearances (ypN0) were seen in 70.0% (21/30) of patients. The most common grade 3-4 treatment-related adverse events in the intention-to-treat population were anemia (2, [6.0%]). Severe treatment-related adverse event included one (3.0%) patient with grade 3 peripheral neuropathy (Guillain-Barré syndrome) and resulted in surgery cancellation. At the time of data cutoff (Feb 7, 2021), the median duration of follow-up was 4.13 months, and there were no treatment-related deaths. Conclusions: Toripalimab plus platinum-based doublet yields a high MPR rate, manageable treatment-related toxicity, and feasible surgical resection in resectable stage III NSCLC. Ongoing analysis of biomarker will be available at the meeting. Clinical trial information: NCT04304248.

First-line pembrolizumab monotherapy for PD-L1-positive (TPS ≥ 50%) advanced non-small cell lung cancer (aNSCLC) in the real world: A national French bispective multicentric cohort—ESCKEYP trial (GFPC 05-2018).

9091 Background: To determine real-world outcomes with first line pembrolizumab monotherapy, for aNSCLC with PD-L1 TPS ≥50%. Methods: Bispective, national and multicentric study including consecutively aNSCLC patients who initiated first-line pembrolizumab monotherapy from May 5, 2017 (marketing authorization of pembrolizumab monotherapy in France) to Nov 22, 2019 (marketing authorization of pembrolizumab-chemotherapy for non-squamous aNSCLC). Data were collected on medical charts. Responses were locally assessed according to RECIST v1.1; overall survival (OS) and real-world progression-free survival (rwPFS) were assessed by Kaplan-Meier method. Results: 845 patients (pts) were included by 33 centres: 67.8% were men, PS 0/1/≥2: 25.5%/46.9%/27.6%, active/former/nonsmokers: 39.1%/51.7%/6.4%, adenocarcinoma: 70.8%; stage IV at diagnosis: 91.6%; median number of metastatic sites at baseline: 2±1 (brain (20.8%), liver (13.9%) and bone (35%)); KRAS mutated: 27.7%, PDL1 TPS > 75%: 53.7% At the cut off date (31 December 2020), on the 783/845 (92.7%) evaluable pts, CR, PR, disease stabilization and progression were reported on 4.7%, 42.6%, 24.1% and 28.6% of cases, respectively; 588 (69.6%) pts had discontinued pembrolizumab, 390 (66.4%) had a first disease progression; 320/390 (82.1%) received a second line treatment, mainly platinum-based chemotherapy (90.6%). With a median follow up of 25,8 [95%CI: 24,8-26,7] months, median rwPFS and median OS were 8,2 [95%CI: 6,9-9,5] and 22,6 [95%CI: 18,5-27,4] months, respectively; 6, 12, 18-months survival rates were 76,8%, 64,8% and 54,3%. 835 adverse events were reported in 48% of the patients, grade ≥3 in 13.8% of cases, mainly asthenia, colitis, pneumonitis. For evaluable patients receiving a platinum-based doublet in second line (266/290, 89%), CR, PR, disease stabilization and progression were reported on 1.9%, 41%, 35.3% and 21.8% of cases, respectively. Uni and multivariate analysis of factors related to OS will be presented at the congress. Conclusions: Despite a less stringent selection of patients, pembrolizumab as a single agent achieves similar tumor shrinkage, rwPFS and OS than those of pivotal clinical trials.

Phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non-small cell lung cancer previously treated with a checkpoint inhibitor: Toxicity update (Lung-MAP non-matched sub-study S1800A).

9075 Background: The therapeutic landscape in metastatic NSCLC has dramatically changed with approvals of immunotherapy agents in both treatment-naïve and previously treated cancer patients (pts) and irrespective of histology. Pts with tumors that develop resistance is a significant area of unmet need. Vascular endothelial growth factor (VEGF) has been shown to modulate the tumor immune microenvironment and combination immune checkpoint and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types. Lung-MAP is a master protocol for pts with stage IV, previously treated NSCLC. Pts who were not eligible for a biomarker-matched substudy enrolled in S1800A. The adverse event profile will be presented. Methods: S1800A is a phase II randomized trial for pts who previously received PD-1 or PD-L1 inhibitor therapy for at least 84 days and platinum-based doublet therapy with ECOG 0-1 stratified by PD-L1 expression, histology and intent to receive ramucirumab in the standard of care (SOC) arm. Pts were randomized 1:1 to pembrolizumab and ramucirumab P+R or SOC (docetaxel +R [SOC w R]; docetaxel, pemetrexed or gemcitabine [SOC wo R]). The primary endpoint was overall survival. Secondary endpoints included response, duration of response, investigator assessed-progression free survival and evaluation of toxicity. Results: From May 17, 2019 to November 16, 2020, 166 pts enrolled and 140 determined eligible [69 (49%) P+R; 46 (33%) SOC w R; 25 (18%) SOC wo R]. Treatments for those who received SOC wo R included 3 on docetaxel (19%); 12 on gemcitabine (75%); and on 1 on pemetrexed (6%). 131 were eligible for adverse event (AE) assessment. The most common AE were fatigue (38%), proteinuria (28%), hypertension (23%), diarrhea (22%) and hypothyroidism (22%) on P+R; fatigue (61%), anemia (48%), diarrhea (41%) and neutropenia (39%) on SOC w R and anemia (56%), leukopenia (56%), fatigue (44%) and neutropenia (44%) on SOC wo R. Grade ≥ 3 treatment-related AEs occurred in 32% of pts on P+R, 54% of pts on SOC w R and 56% of pts on SOC wo R. Cardiac and thromboembolic events occurred in 12% of pts on P+R, 11% of pts on SOC w R and 0% of pts on SOC wo R. Grade 5 AE occurred in 2 pts on P+R (respiratory failure and cardiac arrest), 3 pts on SOC w R (2 respiratory failure and sepsis) and 1 pt on SOC wo R (sepsis). Four patients were diagnosed with COVID-19 (1 on P+R and 3 on SOC) and 3 died (1 on P+R and 2 on SOC). Conclusions: Grade 3 toxicities were lower in P+R compared to SOC arms with or without R. Cardiac and thromboembolic events were similar in arms that included R. P+R was generally well-tolerated. Efficacy outcomes will be presented when data matures. Clinical trial information: NCT03971474.

Role of surgery in a novel multimodal therapeutic approach to complete cure of advanced lung cancer: current and future perspectives.

Non-small cell lung cancer (NSCLC) is considered potentially curable by multimodal therapy in a subset of patients, including those with locally advanced (LA) disease or nodal spread, who would otherwise have a poor prognosis. Guidelines recommend perioperative chemotherapy with platinum-based regimens, with or without radiotherapy, as the standard treatment modality for high-risk resectable LA-NSCLC. Although the classical regimens of adjuvant chemotherapy have been platinum-based doublet or oral agents such as tegafur/uracil, some molecular targeted therapeutic agents and immune checkpoint inhibitors have been developed recently with an expected favorable effect. Recent trials of perioperative therapy using these agents have demonstrated favourable anticancer efficacy for LA-NSCLC with an acceptable adverse events profile. The ideal timing of perioperative therapy administration, before or after surgery, is still controversial. Because some speculation and concepts have arisen from basic research, several trials are ongoing to clarify the efficacy of newly developed agents in the adjuvant or neoadjuvant setting. This review discusses the role of surgery in the new era and analyzes when and which optimal perioperative multimodal therapy, including chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy, should be administered for resectable or potentially resectable NSCLC to provide possible complete cure.

Nab-Paclitaxel Plus Durvalumab in Patients With Previously Treated Advanced Stage Non-small Cell Lung Cancer (ABOUND.2L+).

Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab-paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC.Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab-paclitaxel 100 mg/m2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety.Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred.Conclusions: The nab-paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted.Clinical Trial Registration: ClinicalTrials.gov registration (NCT02250326).EudraCT number: 2014-001105-41

Induction therapy with Erlotinib (E) and Gemcitabine/Platinum (GP) in stage III NSCLC

Background: In 2004 we started a phase II trial in non-small lung cancer (NSCLC), stage III, with erlotinib followed by a combination with a platinum-based doublet in unselected patients to identify molecular subgroups benefitting from an EGFR targeting approach. Patients and methods: Induction with erlotinib (E, 150 mg, d1-42) was followed by three cycles of gemcitabine (G, 1250 mg/m², d1+d8, q3w) and cisplatin (P, 80 mg/m², d1, q3w). Patients with at least stable disease after E were treated with a GP + E combination. Induction was followed by surgery and radiation. The trial was conducted as a prospective, multi-center, open label, exploratory phase II study to determine pathological response rate (pRR), as well as secondary endpoints disease free survival (DFS) and overall survival (OS). Results: Of 38 prescreened patients 16 were included in the main study. Due to slow recruitment the study had to be terminated early. Combination of E and GP was well tolerated, surgery was feasible after induction therapy in 12 of 16 patients, 7/12 (58%) patients had a major pathological response (MPR). Median overall survival for patients with MPR was 57.7 months (confidence interval (CI), 37.4 to 78.0; n = 7) and for patients without MPR 11.9 months (CI, 6.4 to 17.4; n = 5). 2/16 patients had an epidermal growth factor receptor (EGFR) mutation. Conclusion: Before discovery of distinct molecular mechanisms in NSCLC our study was an attempt to identify clinical and pathological subgroups that would benefit from E induction. Two patients with an EGFR mutation were identified. MPR was a predictor of long term disease free and overall survival.