Platinum-pemetrexed Chemotherapy Research Articles

Follow-up after first-Line nivOlumab plus ipilimumab in patients with diffuse pleuRal mesotheliomA: a real-world Dutch cohort study-FLORA.

Diffuse pleural mesothelioma (dPM) is an aggressive malignancy, primarily treated with palliative systemic therapy. Since 2022, nivolumab-ipilimumab (nivo/ipi) has replaced chemotherapy as the standard first-line treatment for dPM in the Netherlands. Chemotherapy remains a rational second-line treatment. The real-world effectiveness of second-line treatment after doublet immunotherapy remains unknown. The FLORA study aimed to provide an overview of treatment patterns in patients with dPM after first-line nivo/ipi and evaluate the effectiveness of second-line chemotherapy based on real-world data. FLORA was a Dutch multicenter retrospective cohort study. Clinical data were collected from the medical records. The primary endpoints were treatment patterns after nivo/ipi and median overall survival (mOS) of patients receiving second-line chemotherapy. The secondary endpoints were objective response rate (ORR), median progression-free survival (mPFS) of second-line chemotherapy, and subgroup analyses (Eastern Cooperative Oncology Group performance status and histological subtype). The study also updated the mOS for first-line nivo/ipi patients. Between May 2021 and July 2023, 277 patients with dPM receiving first-line nivo/ipi therapy were included. Sixty-eight percent of the patients were male, with a median age of 72 years (interquartile range 67-77 years). The histological subtypes were epithelioid (62%), sarcomatoid (22%), biphasic (13%), and unknown (3%). One hundred and two (47%) of the 218 patients with disease progression received second-line treatment, of whom 83 received second-line platinum-pemetrexed chemotherapy. The mOS and mPFS for second-line chemotherapy were 8.2 months ([95% confidence interval (CI) 7.4-9.1 months] and 5.6 months (95% CI 4.9-6.3 months), respectively, with an ORR of 37%. Poor performance score was the main reason for not receiving second-line treatment. This study provides the first real-world data on subsequent treatment of patients with dPM with disease progression on nivo/ipi, resulting in an mOS of 8.2 months after second-line chemotherapy.

The efficacy of continuing osimertinib with platinum pemetrexed chemotherapy upon progression in patients with metastatic non-small cell lung cancer harboring sensitizing EGFR mutations

IntroductionFor patients with EGFR mutant NSCLC who progress on osimertinib, the clinical benefit of continuing osimertinib with next line platinum pemetrexed chemotherapy remains unknown. MethodsIn this international, multi-center, retrospective cohort study, a total of 159 patients with EGFR mutant NSCLC who progressed on osimertinib and received platinum-pemetrexed therapy on progression from 2013 to 2023 were included. The data cutoff was December 31, 2023. Data analysis was conducted from January 2024 to June 2024. The primary endpoints were progression free survival (PFS) and overall survival (OS), analyzed using Kaplan-Meier methods. Multivariable Cox regression adjusting for patient-specific and cancer-specific factors was performed. Results421 patients with EGFR mutant NSCLC with progression on osimertinib were identified, of which159 patients who met pre-specified inclusion criteria were divided into two groups: Cohort 1 (osimertinib + platinum-pemetrexed) included 50 patients (median [IQR] age, 59 [30 – 83] years; 36 [72.0 %] female; 11 [22.4 %] Asian) and Cohort 2 (platinum-pemetrexed alone) included 109 patients (median [IQR] age, 54 [25 – 80] years; 62 [56.9 %] female; 74 [64.9 %] Asian). Most patients were never smokers (Cohort 1, 37 [74.0 %]; Cohort 2, 66 [60.6 %]). One third of patients had baseline brain metastases (Cohort 1, 19 [38.0 %]; Cohort 2, 36 [38.3 %]). Both cohorts had a median of two prior lines of anti-cancer therapy. The addition of bevacizumab or immune checkpoint inhibitors (ICI) to next-line platinum-pemetrexed chemotherapy was more common in Cohort 2 (bevacizumab use, 30.3 % vs 8.0 %, p = 0.002; ICI use, 33.0 % vs 2.0 %, p = 0.001). With a median duration of follow up of 30 months, there was a significant PFS benefit to continuing osimertinib with next line platinum pemetrexed chemotherapy (9.0 vs 4.5 months; HR 0.49, 95 % CI 0.32 – 0.74, p = 0.0032), also seen in subset analyses of patients who received first line osimertinib (n = 55, 11.0 vs 6.2 months; HR 0.41, 95 % CI 0.25 – 0.73, p = 0.002). Among patients with EGFR mutant NSCLC without brain metastases after progression on osimertinib, we found that continuing osimertinib with next line platinum pemetrexed significantly reduced the median time to CNS progression (n = 38; 7.0 vs 4.1 months; HR 0.47, 95 % CI 0.48 – 0.98, p = 0.01). After adjusted analysis, there was no significant OS difference between Cohorts 1 and 2 (19 months vs 13 months; HR 0.92, 95 % CI 0.60 – 1.39, p = 0.68). Conclusions and relevanceFor patients with EGFR mutant NSCLC who progress on osimertinib, there is a significant PFS, but not OS, benefit to continuing osimertinib with next line platinum pemetrexed chemotherapy. The continuation of osimertinib with next line platinum pemetrexed chemotherapy appears to reduce the risk of CNS progression.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC

ObjectivesFirst-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure. Materials and methodsPatients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018–30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS). ResultsA total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0–652) after progression on osimertinib.Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65).TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis. ConclusionsOur real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.

Effect of tumor burden on survival in patients with stage IV EGFR-mutant NSCLC receiving osimertinib monotherapy.

8611 Background: Osimertinib (osi) has traditionally been given as monotherapy for patients (pts) with stage IV EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), although acquired resistance remains a challenge. Recent data from the FLAURA2 study demonstrated a progression free survival (PFS) benefit of approximately 9 months (mos) when osi is combined with platinum-pemetrexed chemotherapy. Despite this improvement, combination therapy is associated with higher rates of adverse events, making it challenging to decide which pts should receive TKI + chemo vs TKI monotherapy. Tumor burden (TB) in pts with stage IV EGFRm NSCLC, which may be associated with risk of developing resistant clones on TKI monotherapy, and its association with clinical outcomes has not been examined. Methods: Retrospective, single institution manual case review of pts who received osi monotherapy. Primary objectives were PFS (i.e., oligoprogression requiring local therapy, disease progression (PD) with osi discontinuation, or death) and overall survival (OS) related to extent of TB. Those who did not receive osi monotherapy for stage IV EGFRm NSCLC or discontinued osi for reasons other than PD were excluded. Demographics, comorbidities, performance status, PD-L1 expression, histology, EGFRm subtype, prior TKI use, total number of visceral tumors (TTn), and total number/sites of metastatic disease (MDn) collected for analysis. Extent of TB categorized by TTn (1-4, 5-9, ≥10) and MDn (1-2, 3-4, ≥5). PFS and OS estimated by Kaplan-Meier method and compared using log-rank test. Results: 325 pts eligible for analysis. Median follow-up time was 22.7 mos. Median PFS (mPFS) for the overall cohort was 16.3 mos (95% CI; 13.7 - 18.9) and median OS (mOS) was 31.1 mos (95% CI; 27.4 - 39.3). Pts with a TTn of 1-4 had significantly better mPFS compared to those with a TTn of 5-9 and ≥10 (mPFS: 21.5 vs 16.3 vs 13.4 mos, respectively; P = 0.001). Pts with a TTn ≥10 had significantly worse mOS compared to those with a TTn of 5-9 and 1-4 (23.7 vs 35.1 vs 57.7 mos, respectively; P < 0.0001). Similarly, pts with a MDn of 1-2 had significantly better mPFS and mOS compared to those with a MDn of 3-4 and ≥5 (mPFS: 21.6 vs 11.4 vs 9.0 mos, respectively [P < 0.0001]; mOS: 44.3 vs 20.8 vs 22.4, respectively [P < 0.0001]). Pts with liver and bone mets had significantly worse mPFS and mOS, whereas those with lung and brain mets had worse mOS without affecting PFS. Conclusions: The extent of baseline TB, categorized by TTn and MDn, impacts both PFS and OS in pts with stage IV EGFRm NSCLC treated with osi monotherapy. Pts with “low-TB” (i.e., TTn 1-4, MDn 1-2) appear to have a survival advantage compared to those with “intermediate- or high-TB” (i.e., TTn 5-9 and ≥10, MDn 3-4 and ≥5) and may derive less benefit from the addition of chemotherapy to osi. Prospective, matched real-world treatment cohorts are warranted to optimize treatment strategies for this patient population.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

e20531 Background: First-line pemetrexed-platinum chemotherapy + osimertinib (Pem-Plat-Osi) improves progression free survival as compared to osimertinib (Osi) alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe the outcomes of patients who receive Pem-Plat-Osi after progression on first-line Osi in 2 tertiary cancer centres. Methods: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line Osi at National Cancer Centre Singapore and Chinese University of Hong Kong were identified. Primary endpoints were time to treatment failure (TTF) and overall survival (OS) by Kaplan-Meier. Results: A total of 60 patients were included. Median age at diagnosis was 62, 53% (32/60) were male and 77% (46/60) were never smokers. Ex19del comprised 57% (34/60) and L858R 43% (26/60). Baseline central nervous system (CNS) metastases were present in 67% (40/60). Median TTF1 on Osi was 12 months (m) and median time to initiation of Pem-Plat-Osi was 41 days (d) (range 0-652) after progression on Osi. CNS failure occurred in 10 patients (16.7%). Partial response (PR) to Pem-Plat-Osi was achieved as best response in 45% (27/60), stable disease in 37% (22/60) and progressive disease in 18% (11/60). Three of 4 patients with CNS PD on Osi who did not undergo brain radiotherapy achieved PR/SD to Pem-Plat-Osi. At median follow up of 31m, median TTF2 on Pem-Plat-Osi was 6m, median TTF1+TTF2 was 20m and median OS was 34m. Comparing ex19del and L858R, there was no significant difference in median TTF1 (10m vs 12m, p=0.63), TTF1+TTF2 (19m vs 21m, p=0.50) and OS (34m vs 36m, p=0.40). Median TTF1+TTF2 (19m vs 20m, p=0.84) and OS (31m vs 36m, p=0.68) were similar in patients with or without baseline CNS metastases. There was no significant difference in TTF2 comparing patients who had TTF1<12m versus TTF1≥12m (both median 6m, p=0.56). Patients who started Pem-Plat-Osi within 20d of progression on Osi had significantly longer TTF2 as compared to patients who started after 20d (median 8m versus 5 months, hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.23-0.89, p=0.016) although there was no significant difference in OS (median 31m versus 34 months, p=0.35). Achieving PR was predictive of superior TTF2 (median 8m vs 5m, HR 0.46, 95% CI 0.26-0.84, p=0.005) but not OS (median 36m vs 32m, p=0.45). Conclusions: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first line Osi, including among L858R subtype and patients with baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression and achieving PR were significantly associated with superior TTF2. Sequential approach of adding chemotherapy upon osimertinib failure is a plausible treatment option.

Targeted Therapy in Mesotheliomas: Uphill All the Way.

Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm.

Abstract CT017: FLAURA2: exploratory analysis of baseline (BL) and on-treatment plasma EGFRm dynamics in patients (pts) with EGFRm advanced NSCLC treated with first-line (1L) osimertinib (osi) ± platinum-pemetrexed

Abstract Background In FLAURA2, 1L osi with addition of platinum-pemetrexed chemotherapy (osi + CTx) significantly improved PFS vs osi alone in pts with EGFRm advanced NSCLC. Prior FLAURA analyses showed detected BL plasma EGFRm to be prognostic and early clearance of plasma EGFRm correlated with improved outcomes. We explored correlation of BL plasma EGFRm detection, and its clearance, with PFS in FLAURA2 to determine its potential to identify pts who derive particular benefit from osi + CTx. Methods Treatment-naïve pts with EGFRm (Ex19del or L858R) advanced NSCLC were randomized to osi + CTx (osi 80 mg once daily [QD] + pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5 every 3 wks [Q3W] for 4 cycles, followed by osi 80 mg QD + pemetrexed 500 mg/m2 Q3W) or osi alone (80 mg QD). BL and wk 3/6 plasma EGFRm were analyzed by ddPCR (Biodesix). Clearance was defined as undetected EGFRm circulating tumor DNA at wk 3/6, where it was detected at BL. Median PFS (mPFS) was investigator-assessed per RECIST 1.1. Results In total, 421/557 pts had an evaluable BL plasma ddPCR result, of who 308 had detected BL plasma EGFRm. Of pts randomized to osi alone, pts with non-detected BL plasma EGFRm had longer mPFS* vs those with detected BL plasma EGFRm. Of pts with evaluable BL and wk 3/6 plasma ddPCR results, plasma EGFRm was detected at wk 3/6 in 19/12% of osi + CTx-treated pts, and 29/11% of osi-treated pts, respectively (Table). Conclusion In this exploratory analysis, detected BL plasma EGFRm was prognostic and appeared predictive of clinical benefit with osi + CTx vs osi alone. Detection of BL plasma EGFRm may identify a subgroup of pts deriving most benefit from the addition of CTx to osi. Although within each treatment arm plasma EGFRm wk3 clearance correlated with improved PFS, the relative benefit of osi + CTx vs osi alone was similar, suggestive that on-treatment EGFRm clearance is only prognostic in this setting. Osimertinib + CTx (evaluable BL ddPCR, n = 212) Osimertinib (evaluable BL ddPCR, n = 209) Osimertinib + CTx vs osimertinib n mPFS (mo) n mPFS (mo) HR (95% CI) Baseline plasma EGFRm Detected 147 24.8 161 13.9* 0.60 (0.45, 0.80) Not detected 65 33.3 48 30.3* 0.93 (0.51, 1.72) EGFRm clearance/non-clearance at 3 weeks Clearance 88 27.6 100 15.2 0.51 (0.35, 0.75) No clearance 21 19.6 40 11.1 0.62 (0.33, 1.14) *Not detected vs detected in the osimertinib arm: mPFS HR 0.51 (95% CI 0.35, 0.76). BL, baseline; CI, confidence interval; CTx, chemotherapy; ddPCR, droplet digital PCR; EGFRm, epidermal growth factor receptor mutation-positive; HR, hazard ratio; mo, months; mPFS, median progression-free survival Citation Format: Pasi A. Jänne, Kunihiko Kobayashi, Jacqulyne Robichaux, Chee Khoon Lee, Shunichi Sugawara, Tsung-Ying Yang, Tae Min Kim, Noriko Yanagitani, Sang-We Kim, Aleksandra Markovets, Preetida Bhetariya, Lynne Poole, Dana Ghiorghiu, Ryan Hartmaier, James Chih-Hsin Yang, David Planchard. FLAURA2: exploratory analysis of baseline (BL) and on-treatment plasma EGFRm dynamics in patients (pts) with EGFRm advanced NSCLC treated with first-line (1L) osimertinib (osi) ± platinum-pemetrexed [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 CT017.

Abstract LB277: Exposure response and safety analysis of osimertinib in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC patients with EGFRm (FLAURA2)

Abstract Osimertinib (Osi) is a potent, CNS-active irreversible inhibitor of epidermal growth factor receptor-mutate (EGFRm) and T790M mutations. It is currently approved as the standard of care in patients with locally advanced (Stage IIIB or IIIC) or metastatic (Stage IV) EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR-TKI therapy and as the first-line agent in patients with locally advanced or metastatic EGFRm NSCLC. FLAURA2 is a global, randomized, open-label, multi-center phase III clinical study to investigate the safety and efficacy of Osi 80 mg once daily in combination with platinum-pemetrexed chemotherapy compared to Osi monotherapy, as a first-line treatment in patients with locally advanced or metastatic EGFRm NSCLC. This study is ongoing and an sNDA has been submitted for approval. The objectives of this current analyses were to 1) assess the exposure-efficacy relationship between population PK model-derived Osi exposure metrics (AUCss, Cmaxss, Cminss), and PFS in patients from the investigational arm (Osi + chemotherapy arm, n=244) of FLAURA2 study and 2) assess the relationship between Osi exposure metrics and key safety endpoints. The exposure response (ER) relationship between Osi and progression free survival (PFS) in patients enrolled in the investigational arm of FLAURA2 was assessed. Kaplan Meier plots with patients stratified by quartile exposure of Osi in the investigational arm indicated no clear ER relationship, though there appears to be a trend of lower PFS with highest AUCss quartile. A stepwise Cox proportional hazard analysis indicated that the effect of Osi exposure metrics were not statistically significant associated with PFS; however, the number of pemetrexed cycles appeared to be a significant covariate on PFS. The relationship between Osi exposure metrics and AEs CTCAE Grade 3 and above causally related to Osi, as well as AESIs from the investigational arm of FLAURA2 study were explored. The graphical exploration and logistic regression analysis did not identify statistically significant relationship of Osi exposures on CTCAE ≥ Grade 3 adverse events (AEs) causally related to Osi, AEs leading to Osi dose interruptions/reductions/discontinuations, and AESIs including ≥ Grade 3 haematological AEs, cardiac effects, left ventricular ejection fraction decrease and ≥ Grade 1 interstitial lung disease causally related to Osi. In conclusions, no statistically significant relationships between exposure of Osi and response were observed, supporting the recommended dose of Osi of 80 mg daily in the FLAURA2 patient population. Overall, the recommended dose of Osi as monotherapy or in combination with chemotherapy is 80 mg once daily, with a dose reduction to 40 mg daily if unacceptable toxicity is observed. Citation Format: Jincheng Yang, Damilola Olabode, Aarti Sawant, Karthick Vishwanathan, Srinivas Bachina, Alexandar Todd, Dana Ghiorghiu, Yuri Rukazenkov, Alex Phipps, Diansong Zhou, Azar Shahraz. Exposure response and safety analysis of osimertinib in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC patients with EGFRm (FLAURA2) [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 LB277.

Updates in Management of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-associated thoracic malignancy that is usually incurable. As demonstrated in the landmark MARS2 trial, surgical resection does not improve survival outcomes and its role in managing MPM is limited. Whilst platinum-pemetrexed chemotherapy in combination with bevacizumab was the standard first-lineapproach for unresectable disease, landmark phase 3 trials have now established the role of immune checkpoint inhibitors (CPIs) in the upfront management of unresectable disease: either nivolumab-ipilimumab or carboplatin-pemetrexed-pembrolizumab. Patient selection for optimal strategy remains an ongoing question. For relapsed disease novel genomic-based therapies targeting a range of aberrations including losses of the tumour suppressor genes BAP1, CDKN2A and NF2, are being evaluated. Nonetheless, the future of MPM therapeutics holds promise. Here we overview current treatment strategies in the management of MPM.

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial

Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma. We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. The Canadian Cancer Society and Merck & Co.

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study

The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy. In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort. Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8-19·4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required. Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma. Merck Sharp & Dohme.

Osimertinib then chemotherapy in EGFR-mutated lung cancer with osimertinib third-line rechallenge (OCELOT).

TPS9160 Background: The results of the FLAURA study established osimertinib as the new first-line standard of care for patients with the two ‘common’ types of epidermal growth factor receptor mutation-positive (EGFR+) advanced non-small-cell lung cancer (aNSCLC). Second-line (2L) treatment is typically platinum pemetrexed chemotherapy and the standard third-line (3L) treatment is docetaxel throughout much of the globe, which has a modest response rate of 7 – 15%. Previously, when first generation (1G) EGFR tyrosine kinase inhibitor (TKIs) were standard of care in the first-line setting, a number of prospective and retrospective studies examined 3L rechallenge with the same 1G EGFR TKI following 2L chemotherapy, with varying levels of success. Osimertinib is a well-tolerated EGFR TKI which is active against the T790M resistance mutation, which would have limited the efficacy of rechallenge with 1G EGFR TKIs. Methods: This is a multicentered international phase II investigator-initiated study of osimertinib in the 3L rechallenge of patients with EGFR+ aNSCLC, following 1L treatment with osimertinib and 2L therapy with platinum pemetrexed chemotherapy. A maximum of 255 patients will be enrolled. Patients with ‘common’ EGFR exon 19 deletions or L858R mutations will enroll at the start of 2L chemotherapy or 3L osimertinib rechallenge. The primary objective is 3L objective response rate (ORR) in the first 100 evaluable patients, according to RECIST 1.1. Secondary objectives include disease control rate (DCR), progression free survival (PFS), time to treatment failure, overall survival and toxicity for 3L osimertinib rechallenge. Exploratory objectives include assessment of osimertinib resistance based on serial ctDNA samples collected from all participants. The OCELOT study, NCT04335292, is actively enrolling participants. Clinical trial information: NCT04335292 .

Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non-Small Cell Lung Cancer: The Piedmont Study.

The Piedmont study is a prospectively designed retrospective evaluation of a new 48-gene antifolate response signature (AF-PRS) in patients with locally advanced/metastatic nonsquamous (NS) non-small cell lung cancer (NSCLC) treated with pemetrexed-containing platinum doublet chemotherapy (PMX-PDC). The study tested the hypothesis that AF-PRS identifies patients with NS-NSCLC who have a higher likelihood of responding positively to PMX-PDC. The goal was to gather clinical evidence supporting AF-PRS as a potential diagnostic test. Residual pretreatment FFPE tumor samples and clinical data were analyzed from 105 patients treated with first-line (1L) PMX-PDC. Ninety-five patients had sufficient RNA sequencing (RNA-seq) data quality and clinical annotation for inclusion in the analysis. Associations between AF-PRS status and associate genes and outcome measures including progression-free survival (PFS) and clinical response were evaluated. Overall, 53% of patients were AF-PRS(+), which was associated with extended PFS, but not overall survival, versus AF-PRS(-) (16.6 months vs. 6.6 months; P = 0.025). In patients who were stage I to III patients at the time of treatment, PFS was further extended in AF-PRS(+) versus AF-PRS(-) (36.2 months vs. 9.3 months; P = 0.03). Complete response (CR) to therapy was noted in 14 of 95 patients. AF-PRS(+) preferentially selected a majority (79%) of CRs, which were evenly split between patients stage I to III (six of seven) and stage IV (five of seven) at the time of treatment. AF-PRS identified a significant population of patients with extended PFS and/or clinical response following PMX-PDC treatment. AF-PRS may be a useful diagnostic test for patients indicated for systemic chemotherapy, especially when determining the optimal PDC regimen for locally advanced disease.

Multi-target angiogenesis inhibitor combined with PD-1 inhibitors may benefit advanced non-small cell lung cancer patients in late line after failure of EGFR-TKI therapy.

Treatments for NSCLC patients with EGFR-TKI resistance are limited. Given that immunotherapy and antiangiogenic agents may have synergistic antitumor effects, we aimed to analyze the effect of multi-target angiogenesis inhibitor anlotinib and immune checkpoint inhibitors (ICIs) combination therapy in NSCLC patients who failed EGFR-TKI. The medical records of lung adenocarcinoma (LUAD) patients with EGFR-TKI resistance were reviewed. After EGFR-TKI resistance, patients who simultaneously received anlotinib and ICIs were enrolled in the observation group, and those who received platinum-pemetrexed chemotherapy were included in the control group. A total of 80 LUAD patients were reviewed and allocated to the anlotinib and ICIs combination therapy (n = 38) and chemotherapy (n = 42) groups. A re-biopsy was performed in all patients in the observation group before the administration of anlotinib and ICIs. The median follow-up was 15.63 months (95% CI: 12.19-19.08). Combination therapy exhibited better PFS (median PFS: 4.33 months [95% CI: 2.62-6.05] vs 3.60 months [95% CI: 2.48-4.73], P = .005), and better OS (median OS: 14.17 months [95% CI: 10.17-18.17] vs 9.00 months [95% CI: 6.92-11.08], P = .029) than chemotherapy. Most patients (73.7%) received combination therapy as fourth and later lines of therapy, with a median PFS of 4.03 months (95% CI: 2.05-6.02) and a median OS of 13.80 months (95% CI: 8.25-19.36). The disease control rate was 92.1%. Four patients discontinued the combination therapy due to adverse events, but the other adverse reactions were manageable and reversible. The combination of anlotinib and PD-1 inhibitors is a promising regimen for the late-line treatment of LUAD patients with EGFR-TKI resistance.

Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a cancer with a high mortality rate and few therapeutic options. After platinum-pemetrexed combination, no further promising drug seems to be effective. Immune checkpoint inhibitors may have some activity in pretreated patients and no data are available in this population about durvalumab. DIADEM was a multicenter, open-label, single-arm, phase II trial aimed at evaluating the efficacy and safety of durvalumab. Patients with locally advanced/metastatic MPM who progressed after platinum-pemetrexed chemotherapy were enrolled to receive durvalumab (1500 mg, intravenously Q4W) for 12 months or until evidence of disease progression or unacceptable toxicity. The primary endpoint was the proportion of patients alive and free from progression at 16 weeks (PFS16wks) calculated from treatment initiation. Secondary endpoints were progression-free survival, overall survival, overall response rate, and safety. Sixty-nine patients with a median age of 69 years (range 44-82 years) were enrolled; 62 patients (89.9%) had epithelioid histotype. As first-line treatment, all patients received platinum derivatives-pemetrexed combination (60.9% with carboplatin and 39.1% with cisplatin). As of March 2021, the median follow-up was 9.2 months (interquartile range 5.2-11.1 months). Six patients (8.7%) completed the 12-month treatment; 60 patients discontinued, of whom 42 for progressive disease, and 4 died. Seventeen patients (28.3%; 95% confidence interval 17.5% to 41.4%) were alive or free from progression at 16 weeks. Eleven patients (18.6%) had a grade 3 or 4 treatment-related adverse event (AE), and one (1.4%) had a grade ≥3 immune-related, treatment-related AE. There was one drug-related death. Durvalumab alone in pretreated non-selected MPM did not reach a meaningful clinical activity, showing any new major safety issue signals.

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

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

EP08.02-034 OCELOT - Osimertinib then Chemotherapy in EGFR+ Lung Cancer with Osi Third-line Rechallenge and Osimertinib for Uncommon EGFRm in 1L

The FLAURA study established osimertinib as a preferred first-line standard of care for patients with the two ‘common’ types of epidermal growth factor receptor mutation-positive (EGFR+) advanced non-small-cell lung cancer (aNSCLC). Second-line (2L) treatment is typically platinum pemetrexed chemotherapy and the standard third-line (3L) treatment is docetaxel, which has a modest response rate of 7 - 15%. Previously, when first generation (1G) EGFR tyrosine kinase inhibitors (TKIs) were standard of care in the first-line setting, a number of prospective and retrospective studies examined 3L rechallenge with the same 1G EGFR TKI following 2L chemotherapy, with varying levels of success.

The Cost-Effectiveness of Tislelizumab Plus Chemotherapy for Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer.

Objective: To investigate the cost-effectiveness of adding Chinese-developed anti-PD-1 antibody tislelizumab to first-line pemetrexed-platinum chemotherapy in (1) a study population of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (nsqNSCLC) and without known sensitizing EGFR mutations or ALK rearrangements and (2) its subgroups from the perspective of Chinese healthcare system. Material and Methods: Separate Markov models were constructed for the entire study population and its subgroups; 10,000 patients with locally advanced or metastatic nsqNSCLC and without driver gene mutations were simulated in the first-line tislelizumab plus pemetrexed-platinum (TPP) arm and first-line pemetrexed-platinum (PP) arm, respectively. Transition probabilities were extracted from the RATIONALE 304 trial. Public health state utilities and costs were obtained from published literature, public national databases, and local general hospitals. The main outputs were incremental cost-effectiveness ratios (ICERs). The ICERs were compared to a willingness-to-pay threshold of $35,663 per quality-adjusted life-years (QALYs) to determine the cost-effective treatment. Sensitivity analyses were employed to assess the uncertainty in the model. Results: For the entire patient population, first-line TPP versus PP use increased the effectiveness by 0.99 QALYs and healthcare costs by $28,749, resulting in an ICER of $28,749/QALY that was lower than the prespecified WTP threshold. For patient subgroups, first-line TPP conferred the greatest survival benefit in patients with PD-L1 expression ≥50%, followed by patients with liver metastasis and those who are current or former smokers. Overall, the ICERs for the first-line TPP versus PP ranged from $27,018/QALYs to $33,074/QALYs, which were consistently below the WTP threshold. Conclusion: For Chinese patients with locally advanced or metastatic nsqNSCLC who had no known sensitizing EGFR mutations or ALK rearrangements, adding the Chinese-developed anti-PD-1 antibody tislelizumab to the first-line pemetrexed-platinum chemotherapy was cost-effective regardless of their baseline characteristics.

Abstract CT559: Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification

Abstract Background: MET amplification can arise as a bypass resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) and occurs in ~5-26% of EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). These patients (pts) have limited treatment options, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in more than 10 countries for the treatment of metastatic MET exon 14 skipping NSCLC. In preliminary studies, capmatinib plus EGFR TKIs showed antitumor activity in the post-EGFR TKI, EGFR-mutant NSCLC setting. GEOMETRY-E (NCT04816214) is a randomized, controlled, open-label, multicenter, phase 3 study evaluating the efficacy and safety of capmatinib + osimertinib vs platinum-pemetrexed doublet chemotherapy as second line treatment in the advanced NSCLC setting. Methods: This ongoing study began enrollment in September 2021 and is recruiting adult pts with stage IIIB/IIIC or IV EGFR-mutant, T790M−, MET-amplified NSCLC who had progressed on either 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs. Pts with neurologically unstable, symptomatic CNS metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are ineligible. This is a 2-part study where Part 1 (initial run-in, ~10 pts) will confirm the recommended dose for the randomized Part 2 and evaluate the safety and tolerability of capmatinib + osimertinib. In Part 1, pts will receive oral capmatinib 400 mg twice daily + osimertinib 80 mg once daily in 21-day cycles. Part 2 will evaluate the efficacy and safety of capmatinib + osimertinib vs platinum (cisplatin/carboplatin)-pemetrexed. Part 2 will enroll ~225 pts, in 2:1 randomization, stratified by the presence of brain metastases (yes/no) and prior treatment with 3rd generation EGFR TKIs (yes/no). In Part 1, the primary endpoint is the incidence of dose limiting toxicities during the first 21 days of treatment. Secondary endpoints include safety; tolerability; pharmacokinetics (PK); investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), disease control rate (DCR) and progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). In Part 2, the primary endpoint is blinded independent review committee (BIRC)-assessed PFS per RECIST 1.1. The key secondary endpoints are ORR by BIRC per RECIST 1.1 and overall intracranial response rate (OiRR) by BIRC per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Other secondary endpoints include DOR, TTR and DCR by BIRC; investigator-assessed PFS after next line of treatment; PK; safety; overall survival; patient-reported outcomes; intracranial DCR, duration of and time to intracranial response by BIRC per RANO-BM. Citation Format: Yi-Long Wu, Ji-Youn Han, Terufumi Kato, Fabrice Barlesi, Edward B. Garon, Federico Cappuzzo, Yuji Shibata, Nathalie Smith, Sadhvi Khanna, Riccardo Belli, Alejandro Yovine, Daniel Tan. Capmatinib plus osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in patients with stage IIIB/IIIC or IV EGFR-mutant, T790M-negative NSCLC harboring MET amplification [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 CT559.

Abstract 1296: MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells

Abstract Chemotherapy with anti PD-1/PD-L1 mAb has become the standard of care for patients with metastatic non-small cell lung cancer (NSCLC). Using lung tumor models, where pemetrexed-platinum chemotherapy (PEM/CDDP) remains unable to synergize with immune checkpoint inhibitors (ICI), we linked failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, and restores ICI efficacy. PEM/CDDP plus MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA and TLR9-dependent manner. TLR9 or autophagy/mitophagy processes genetic inactivation of abort the antitumor efficacy of PEM/CDDP plus MEKi/anti PD-L1 therapy. In human NSCLC, high OPTN, TLR9 and CXCL10 expression is associated with better response to ICI. Our results underline the role of TLR9 and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy. Citation Format: Emeric Limagne, Lisa Nuttin, Marion Thibaudin, Elise Jacquin, Romain Aucagne, Marjorie Bon, Elise Ballot, Solène Revy, Robby Barnestein, Caroline Truntzer, Valentin Derangère, Jean-David Fumet, Rébé Cédric, Pierre-Simon Bellaye, Coureche-Guillaume Kaderbhai, Aodrenn Spill, Bertrand Collin, Mary Callanan, Aurélie Lagrange, Laure Favier, Bruno Coudert, Laurent Arnould, Sylvain Ladoire, Bertrand Routy, Philippe Joubert, François Ghiringhelli. MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells [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 1296.