Maintenance Pemetrexed Research Articles

Pemetrexed maintenance with or without pembrolizumab in non-squamous non-small cell lung cancer: A cross-trial comparison of KEYNOTE-189 versus PARAMOUNT, PRONOUNCE, and JVBL

ObjectiveTo characterize the benefit-risk profile of pemetrexed and platinum in combination with pembrolizumab in patients with non-squamous non-small cell lung cancer in the KEYNOTE-189 study, with reference to historical pemetrexed maintenance data from the PARAMOUNT, PRONOUNCE, and JVBL randomized studies. Materials and methodsTo harmonize the treatment setting across the studies in our comparative analysis, we selected patients from KEYNOTE-189 who received ≥5 cycles of pemetrexed (pembrolizumab/pemetrexed/platinum, N = 310; placebo/pemetrexed/platinum, N = 135) and pooled data from PARAMOUNT (N = 359), PRONOUNCE (N = 98), and JVBL (N = 29) who received ≥5 cycles of pemetrexed (total, N = 486). For the 2 selected populations from KEYNOTE-189 and the pooled historical data, progression-free survival (PFS) was evaluated by Kaplan-Meier estimator and Cox proportional hazards model. Tumor response and grade ≥3 treatment-emergent adverse events (TEAEs) for the aforementioned population were summarized by descriptive statistics. ResultsIn the selected KEYNOTE-189 population with ≥5 cycles pemetrexed, median PFS was 9.3 months (95 % confidence interval [CI]: 9.0–11.1) in the pembrolizumab/pemetrexed/platinum arm and 6.6 months (95 % CI: 5.4–7.1) in the placebo/pemetrexed/platinum arm (unstratified hazard ratio: 0.53; 95 % CI: 0.42‒0.68; p ≤ 0.0001). In the pooled population with ≥5 cycles pemetrexed from historical trials, median PFS was 5.6 months (95 % CI: 4.6–5.8). Objective response rates were 58.7 % and 28.9 % in the pembrolizumab/pemetrexed/platinum and placebo/pemetrexed/platinum arms, respectively, of KEYNOTE-189 and 42.4 % in the pooled historical studies. The incidence of grade ≥3 TEAEs was similar in both arms of KEYNOTE-189 and in the pooled historical studies. ConclusionImproved PFS was shown with pembrolizumab/pemetrexed/platinum compared with placebo/pemetrexed/platinum in the patient group with pemetrexed maintenance (≥5 cycles) in KEYNOTE-189. The PFS and safety profile of the control arm in KEYNOTE-189 were comparable with historical pemetrexed maintenance data.

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC.

In cohort G of KEYNOTE-021 (NCT02039674), first-line pembrolizumab plus pemetrexed-carboplatin significantly improved the objective response rate and progression-free survival versus chemotherapy alone with manageable toxicity in advanced nonsquamous NSCLC. We report the long-term outcomes from this study. Patients with previously untreated advanced nonsquamous NSCLC without sensitizing EGFR or ALK alterations were randomly assigned 1:1 to receive open-label pemetrexed 500 mg/m2 plus carboplatin at area under the concentration-time curve of 5 mg/mL/min (four cycles) with or without pembrolizumab 200 mg (up to 2 years), with optional pemetrexed maintenance, each administered every 3 weeks. Eligible patients could crossover from the chemotherapy arm to pembrolizumab monotherapy after progression. Responses were assessed per the Response Evaluation Criteria in Solid Tumors version 1.1. After the median time of 49.4 months from randomization to data cutoff, objective response rate (58% versus 33%) and progression-free survival (median: 24.5 versus 9.9 mo; hazard ratio: 0.54; 95% confidence interval: 0.35‒0.83) remained improved with pembrolizumab combination (n= 60) versus chemotherapy (n= 63), regardless of programmed death ligand 1 status. Median overall survival was 34.5 versus 21.1 months (hazard ratio: 0.71; 95% confidence interval: 0.45‒1.12), despite a 70% crossover rate from chemotherapy alone to anti‒programmed death (ligand) 1 therapy. Among the 12 patients who completed 2years of pembrolizumab, 92% were alive at data cutoff; the estimated 3-year duration of response rate was 100%. Grade 3 to 5 treatment-related adverse events occurred in 39% of patients receiving pembrolizumab combination and 31% receiving chemotherapy. First-line pembrolizumab plus pemetrexed-carboplatin continued to show improved response and survival versus chemotherapy alone in advanced nonsquamous NSCLC, with durable clinical benefit in patients who completed 2 years of therapy. No new safety signals were observed with longer follow-up.

PD-L1 expression is a promising predictor of survival in patients with advanced lung adenocarcinoma undergoing pemetrexed maintenance therapy

This study aimed to identify potential predictive factors for the survival of advanced lung adenocarcinoma patients undergoing pemetrexed maintenance therapy. 122 advanced lung adenocarcinoma patients who received pemetrexed maintenance therapy were retrospectively analyzed. Kaplan–Meier method with Log-rank test was used for survival analysis. Univariate and multivariate Cox regression were performed to evaluate prognostic factors for overall survival (OS) and progression-free survival (PFS). Bivariate correlation analysis was used for exploratory purpose. For the whole cohort of 122 patients, median PFS was 11.97 months (95% CI 10.611–13.329) and estimated median OS was 45.07 months (95% CI 31.690–58.450). The mPFS of ALK-positive patients was superior to negative patients (18.27 vs. 11.90 months; P = 0.039). Patients with ECOG PS 0 (14.4 vs. 11.1 months; p = 0.040) and patients with single-organ metastasis (19.0 vs. 11.0 months; p = 0.014) had prolonged median PFS. Compared with the low PD-L1 expression group, PFS of high PD-L1 expression group were improved (13.6 vs. 11.1 months, p = 0.104, at 1% cut-off; 17.5 vs. 11.1 months, p = 0.009, at 10% cut-off; and 27.5 vs. 11.4 months, p = 0.005, at 50% cut-off). No differences were found between EGFR positive and negative patients. PD-L1 expression was an independent prognostic factor for both PFS and OS times (PFS: HR, 0.175; P = 0.001; OS: HR, 0.107; P = 0.036). Bivariate correlation showed a significant positive correlation between PD-L1 expression and PFS (correlation coefficient R = 0.485, P < 0.001). High PD-L1 expression could be a potential effective predictor for favorable survival of advanced lung adenocarcinoma patients undergoing pemetrexed maintenance therapy.

Systemic Immune-inflammation Index is the Best Prognostic Factor in Patients with Advanced Stage Adenocarcinoma of the Lung Treated with Pemetrexed.

To evaluate the prognostic role of systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in patients who received platin-pemetrexed combination therapy and/or maintenance pemetrexed therapy. Observational study. Department of Medical Oncology, HSU Dr. Abdurrahman Yurtaslan Oncology, Training and Research Hospital, Turkey, between January 2010 and March 2020. Data of patients with metastatic adenocarcinoma of lung, who underwent platin-pemetrexed combination therapy and/or maintenance pemetrexed therapy retrospectively, were evaluated. Patient characteristics and disease parameters were recorded. Moreover, NLR, PLR, and SII were calculated. Survival analysis with the Kaplan-Meier and Log-rank test was performed. Cox regression analysis was used to determine independent prognostic factors of overall survivall (OS) and progression-free survival (PFS). In the univariate analyses, NLR-low group and SII-low group had significantly longer PFS compared to NLR-high and SII-high groups (10 months vs. 8 months, p=0.018, and 13 months vs. 8 months, p<0.001, respectively). The significant differences were seen between SII-low and SII-high groups for OS (24 months vs. 13 months, p=0.001). In multivariate analyses, response to treatment and low-SII were independent prognostic factors for PFS (HR: 0.25, p<0.001, and HR: 0.47, p=0.002, respectively) and OS (HR: 2.09, p=0.001, and HR: 2.05, p=0.001, respectively). Conclusion: SII is the most powerful of the three studied inflammatory indices, which could independently predict overall and progression-free survival. Key Words: Systemic immune-inflammation index, Neutrophil-to-lymphocyte ratio, Platelet-to-lymphocyte ratio, Adenocarcinoma, Lung cancer, Pemetrexed.

Randomized phase III trial comparing switch-maintenance pemetrexed with observation followed by pemetrexed at progression in advanced NSCLC

Objectives: Two phase III trials show that maintenance pemetrexed therapy after platinum-doublet chemotherapy prolongs overall survival (OS) and progression free survival (PFS) in advanced non-squamous non-small-cell lung cancer (NSCLC). However, few patients in the control arms received pemetrexed at progression in these trials, performance status (PS) two patients were ineligible and few of the participants were elderly. Thus, we designed this study comparing immediate switch-maintenance pemetrexed therapy with pemetrexed at progression after platinum-doublet chemotherapy.Methods: Patients with stage IIIB/IV non-squamous NSCLC, ≥18 years, PS 0–2, and non-progression after four courses of carboplatin/vinorelbine were randomized to receive immediate maintenance pemetrexed therapy or observation followed by pemetrexed at progression. The primary endpoint was OS, secondary endpoints were PFS, toxicity and health related quality of life (HRQoL).Results: 105 patients were randomized between May 2014 and September 2017. Median age was 67 years, 36% were >70 years, 9% had PS 2, 91% stage IV and 47% were women. In the observation arm, 73% received pemetrexed at progression. Patients in the maintenance arm had a numerically longer OS (median 12.0 vs. 10.0 months; p = .10) and a statistically significant longer PFS (median 3.1 vs. 1.9 months; p < .01). In multivariable analyses adjusting for baseline characteristics, there was a trend toward improved OS (HR 0.65, 95% CI 0.42–1.01); p = .05), and a significantly improved PFS (HR 0.53, 95% CI 0.35–0.80; p < .01). There were no significant differences in toxicity or HRQoL between the treatment arms.Conclusion: There was a trend toward prolonged OS and significantly longer PFS from switch- maintenance pemetrexed therapy when 73% of patients in the control arm received pemetrexed at progression. ClinicalTrials.gov Identifier: NCT02004184

AcceleRET Lung: A phase III study of first-line pralsetinib in patients (pts) with RET-fusion+ advanced/metastatic non-small cell lung cancer (NSCLC).

TPS9633 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1-2% of NSCLC, but no selective RET inhibitors are approved for use. The investigational RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multikinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), pts with RET-fusion+ NSCLC treated with 400 mg once daily (QD) of pralsetinib (N = 80) after platinum-based chemotherapy achieved an overall response rate (ORR) of 61% (95% CI 50, 72; 2 responses pending confirmation) per independent central review. In addition, a promising ORR of 73% (all centrally confirmed responses) was attained in the treatment naïve cohort (N = 26). Most treatment-related adverse events were grade 1-2 across the entire safety population treated at 400 mg QD (N = 354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). Methods: Approximately 250 pts with metastatic RET-fusion+ NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and ECOG PS. Key eligibility criteria include no prior systemic treatment for metastatic disease; RET-fusion+ tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per RECIST v1.1. Pts randomized to SOC will be permitted to cross-over to receive pralsetinib upon disease progression. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Recruitment has begun with sites (active or planned) in North America, Europe and Asia. Clinical trial information: NCT04222972 .

CCTG BR.34: A randomized trial of durvalumab and tremelimumab +/- platinum-based chemotherapy in patients with metastatic (Stage IV) squamous or nonsquamous non-small cell lung cancer (NSCLC).

9502 Background: First-line therapy for advanced NSCLC includes PD-1 checkpoint inhibitor (ICI) monotherapy, and in combination with chemotherapy. Combination ICI have also demonstrated better survival compared to chemotherapy (CM-227). In CCTG BR.34, we compared overall survival (OS) in patients with advanced NSCLC receiving first-line durvalumab plus tremelimumab (DT) with or without platinum doublet chemotherapy (CT). Methods: This international, open-label, randomized trial accrued 301 participants from Canada and Australia, with stage IV NSCLC, EGFR/ALK wildtype, ECOG PS 0/1. Patients were randomized to DT for 4 cycles or DT+CT (pemetrexed- or gemcitabine-platinum), with ongoing D or D + pemetrexed (non-squamous) maintenance until disease progression. Stratification factors included histology, stage IVA v. IVB and smoking status. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR = CR + PR) and adverse events (AEs). Results: At a median follow up of 16.6 months, no significant difference in OS was seen between the two treatment arms, with a median OS of 16.6 months with DT+CT v. 14.1 months with DT, (estimated HR 0.88, 90% CI 0.67-1.16). PFS was significantly improved in the DT+CT arm (stratified HR 0.67, 95% CI 0.52-0.88; medians 7.7 v. 3.2 months). ORR was higher in the DT+CT arm, 28% v. 14%, (odds ratio 2.1, p=0.001). Preplanned subgroup analysis demonstrated no significant differences in treatment outcomes by plasma TMB (&lt;20 v. ≥20 mut/Mb, Guardant OMNI), age, sex, or smoking status. There was a trend to improved OS with DT+CT in the subgroup with PD-L1 TPS≥50%, (HR 0.64, 95% CI 0.40-1.04, p=0.07). Plasma TMB&lt;20 mut/Mb was associated with shorter survival in both treatment groups (HR 1.99, 95% 1.3-3.1). Toxicity was greater in the DT+CT arm, with grade≥3 adverse events in 82% v. 70%, (p=0.02), most commonly dyspnea, nausea and cough. The incidence of immune-related adverse events was similar between arms (colitis 11%, pneumonitis 6%, endocrinopathy 21%). Grade 5 events occurred in 2.7%, (5 with DT+CT, 3 with DT). Conclusions: The addition of CT to first-line DT did not improve OS in advanced NSCLC. CT+DT improved ORR and PFS, and was associated with greater toxicity. No differential effects were seen by PD-L1 TPS nor bTMB. These data suggest that adding chemotherapy to ICI may be beneficial in those with PD-L1 TPS &gt;=50%, and warrant further analysis in independent datasets. Clinical trial information: NCT03057106 .

Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA.

9501 Background: NIVO + IPI was shown to improve overall survival (OS) and durability of response vs chemo in 1L advanced NSCLC in CheckMate 227 Part 1, regardless of PD-L1 expression. We hypothesized that a limited course of chemo combined with NIVO + IPI could provide rapid disease control while building on the durable OS benefit seen with dual PD-1 and CTLA-4 inhibition. CheckMate 9LA (NCT03215706) is a phase 3 randomized study evaluating NIVO + IPI + 2 cycles chemo vs chemo in 1L stage IV/recurrent NSCLC. Methods: Adults with tx-naive, histologically confirmed stage IV/recurrent NSCLC, ECOG performance status 0–1, and no known sensitizing EGFR/ALK alterations were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (&lt; 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous). Chemo was based on histology. Pts with non-squamous NSCLC in the chemo-only arm could receive optional pemetrexed maintenance. Pts were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 y. The primary endpoint was OS; the interim analysis using Lan–DeMets alpha spending function with O’Brien–Fleming boundary was planned at ~80% information fraction (ie, after observing ~322 total events). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability. Results: Baseline characteristics were balanced across arms. At a preplanned interim analysis (minimum follow-up 8.1 mo), OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen. With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology. Grade 3–4 tx-related adverse events were reported in 47 vs 38% of pts in the NIVO + IPI + chemo vs chemo arms, respectively. Conclusions: CheckMate 9LA met its primary endpoint: a statistically significant improvement in OS was observed with NIVO + NSCLC-optimized IPI + a limited course of chemo vs chemo (4 cycles) in 1L advanced NSCLC. No new safety signals were reported. Clinical trial information: NCT03215706 .

Randomized phase 3 open label study of quality of life of patients on Pemetrexed versus Erlotinib as maintenance therapy for advanced non squamous non EGFR mutated non small cell lung cancer.

Background: We planned to compare pemetrexed maintenance with erlotinib maintenance in non squamous non Epidermal Growth Factor Receptor (EGFR) mutated non small cell lung cancer (NSCLC). The null hypothesis for this study was that there would be no difference in quality of life (QOL) between pemetrexed and erlotinib maintenance. Results: The QL2 scores at 3 months were 63.35 (SD 24.99) in pemetrexed arm and 63.01(SD 23.04) in erlotinib arm (p-0.793). Except in 1 domain, the scores were statistically similar between the 2 arms. In the domain of diarrhea, the score was higher as expected in the erlotinib arm (p-0.048). The median progression free survival was 4.5 months (95%CI 4.1–4.9 months) in pemetrexed arm versus 4.5 months (95%CI 3.8–5.2 months) in erlotinib arm (p-0.94). The median overall survival was 16.6 months (15.2–17.9 months) in pemetrexed arm versus 18.3 months (95% CI 13.75–22.91 months) in erlotinib arm (p-0.49). Methods: The study was an open label, single centre, parallel, phase 3 randomized study with 1:1 randomization between maintenance pemetrexed arm and erlotinib arm. Adult patients (age > or = 18 years), with non squamous EGFR mutation, treated with first line palliative therapy, with non progressive disease post 4–6 cycles of pemetrexed-carboplatin were randomized. Primary outcome was change in the score of QOL (Global health status {QL2}) at 3 months. We estimated that with 200 patients, the study had 80% power to detect a significant difference between the two groups in the change in the global health status score at 3 months with an alpha error of 5%, with an effect size of 0.3 SD. Conclusions: Maintenance pemetrexed post pemetrexed-platinum chemotherapy fails to improve QOL or time to event outcomes over maintenance erlotinib in EGFR mutation negative NSCLC.

Antitumor effect of immune checkpoint inhibitor for subsequent therapy

Abstract Background The pathway consisting of the receptor programmed cell death 1 (PD-1) and its ligands plays a crucial role to escape T cell-mediated immunity. Antibodies targeting PD-1 and its ligands have beneficial antitumor effects on many cancers, and some cases show long-time survival. Methods We retrospectively reviewed medical records of non-small cell lung cancer (NSCLC), head and neck cancer, and renal cancer patients who received subsequent therapy (chemotherapy or targeted therapy) after the administration of anti PD-1 or PD-L1 antibody between January 2016 and December 2018 at Okazaki City Hospital. Subsequent therapy included S-1, Pemetrexed (PEM), Cisplatin (CDDP) +PEM +Bevacizumab (BV) and PEM +BV maintenance, Carboplatin (CBDCA) +PEM and PEM maintenance, weekly Paclitaxel (wPTX), Docetaxel (DTX), Everolimus and Pazopanib. The latest analysis was performed in June 2019. Results Of the 13 patients who had received anti PD-1 antibody (NSCLC/head and neck cancer/renal cancer, 7/3/3; Nivolumab/Pembrolizumab, 10/3), 2 had partial response and 7 had stable disease for the 1st line subsequent therapy (overall response rate, 15%; disease control rate, 69%). Duration of median progression free survival (PFS) at the therapy was 10.9 m (S-1 in NSCLC), 16.0 m (CDDP+PEM+BV and PEM+BV maintenance), NE (PEM), 6.2 m (CBDCA+ PEM and PEM maintenance), 5.0 m (wPTX), 0.5 m (DTX), 6.0 m (Everolimus) and 14.1 m (Pazopanib) each. Median overall survival was 14.0 m, and 7 of the 13 patients were still alive. Two patients with Grade 2 interstitial lung disease due to Everolimus and PEM were successfully treated. Conclusion PFS of S-1 in NSCLC after the administration of anti PD-1 antibody was longer than that of the East Asia S-1 Trial in Lung Cancer. Interstitial lung disease due to targeted therapy was successfully managed.

MON-253 PEMETREXED INDUCED INTERSTITIAL NEPHRITIS AMONG PATIENTS WITH METASTATIC NON-SMALL CELL ADENOCARCINOMA OF THE LUNGS (NSCLC)

Pemetrexed, a folate antagonistic chemotherapy, was approved for metastatic NSCLC since 2008. We documented 3 cases of biopsy-proven interstitial nephritis treated with pemetrexed. Interstitial nephritis had been described but incidence is unknown. Case 1: A 48-year-old African man with obesity and glucose intolerance presented with protracted cough. Investigation showed locally advanced NSCLC (EGFR +ve). Treatment with gefitinib failed showing progression. He developed right malignant pleural effusion and bilateral lung nodules. Baseline serum creatinine was 120 µmol/L. Pemetrexed was started 14 months after diagnosis. He received dexamethasone initially. Disease progression was halted after 4 cycles. Serum creatinine rose to 188 µmol/L after treatment for 20 months with interruptions. Renal biopsy showing chronic tubulointerstitial nephritis. Pemetrexed was stopped and azathioprine was given for several weeks. Renal function stabilized. Chemotherapy was changed to erlotinib, but he died 6 months later. Case 2: A 63-year-old Caucasian lady with chronic smoking and type I diabetes mellitus was diagnosed with metastatic NSCLC with left lung masses, EGFR/ALK negative. She was started on cis-platinum/pemetrexed. The baseline serum creatinine was 70 µmol/L. She received 4 doses of cisplatin/pemetrexed with good response. Then she was maintained on pemetrexed and received 4 more cycles. her serum creatinine increased to 296 µmol/L. She had a percutaneous renal biopsy showing acute interstitial nephritis most likely from pemetrexed. Confounding drugs include esomeprazole and venlafaxine. She received 4 months of tapering prednisone with cessation of Pemetrexed. The serum creatinine stabilized between 210-230 µmol/L. Follow-up staging showed little progression of her pulmonary locally advanced metastasis. Case 3: A 65-year-old female chronic smoker was diagnosed to have metastatic NSCLC (EGFR/ALK negative) with large lung masses, supraclavicular lymph nodes, occipital lytic lesion and 20 kg weight loss. Baseline serum creatinine was 49 µmol/L. She was started on carboplatin/pemetrexed. She had 4 courses in 3 months and tolerated treatment very well. She gained weight with good appetite and energy. She was started on maintenance pemetrexed. 4 months after starting chemotherapy, serum creatinine rose to 149 µmol/L. Pemetrexed was halted and renal biopsy showed mild active tubulointerstitial nephritis. Serum creatinine stabilized at 100 µmol/L. We proposed to restart pemetrexed with covering prednisone. Unfortunately, the metastatic lesions led to her demise quickly. Our 3 cases indicated beneficial effect of pemetrexed for metastatic NSCLC. However, it can lead to tubulointerstitial nephritis and loss of renal function. Cessation of pemetrexed terminated the beneficial effects and led to metastatic progression. Prednisone or azathioprine can be considered for immunosuppression while patients continued pemetrexed, deriving beneficial therapeutic effect. A pemetrexed registry could be helpful to document incidence, clinical course and treatment possibilities of tubulointerstitial nephritis.

Abstract CT043: Outcomes among patients (pts) with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab (pembro) plus pemetrexed-platinum: Results from the KEYNOTE-189 study

Abstract Background: KEYNOTE-189 is a randomized, placebo-controlled, Phase III study of pembro plus pemetrexed-platinum versus placebo plus pemetrexed-platinum among pts with metastatic nonsquamous NSCLC. At median follow-up of 10.5 months, pts in the pembro-combination arm had improved OS (HR, 0.49; 95% CI, 0.38-0.64; P&amp;lt;0.001) and PFS (HR, 0.52; 95% CI, 0.43-0.64; P&amp;lt;0.001) compared with pts in the placebo-combination arm. We present a retrospective, exploratory evaluation of outcomes among pts with liver and brain metastases at baseline from an updated analysis. Methods: Pts with untreated metastatic nonsquamous NSCLC, ECOG PS 0/1, and without EGFR/ALK alteration were randomized 2:1 to receive up to 35 Q3W cycles of pembro 200 mg or placebo plus 4 cycles of pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 followed by maintenance pemetrexed. Randomization was stratified by PD-L1 TPS (&amp;lt;1% vs ≥1%), platinum (carboplatin vs cisplatin), and smoking status (current/former vs never). Response was assessed by RECIST v1.1 per blinded, independent central review. OS and PFS were primary endpoints. Results: 616 pts were randomized (pembro-combination, n=410; placebo-combination, n=206). At data cutoff, median follow-up was 18.7 months. At baseline, 19% of pts had liver metastases and 18% had brain metastases. HRs for OS and PFS favored the pembro-combination vs placebo-combination across all groups, and were similar for pts with/without liver or brain metastases (Table). Conclusion: Pembro plus pemetrexed-platinum provided superior outcomes vs chemotherapy alone irrespective of liver or brain metastases in pts with untreated metastatic nonsquamous NSCLC. Benefit was observed in pts with brain or liver metastases, for whom prognosis is historically poor. PFSOSN*Median, mo (95% CI)HR(95% CI)Median, mo (95% CI)HR(95% CI)Pts With Liver MetastasesPembro-combination666.1 (4.7-8.5)0.52 (0.34-0.81)12.6 (8.1-19.1)0.62 (0.39-0.98)Placebo-combination493.4 (2.8-4.7)6.6 (4.6-7.6)Pts Without Liver MetastasesPembro-combination3449.2 (8.8-11.0)0.48 (0.39-0.59)23.7 (20.1-25.9)0.58 (0.45-0.74)Placebo-combination1575.4 (4.9-6.7)13.2 (10.0-16.4)Pts With Brain MetastasesPembro-combination736.9 (5.4-11.0)0.42 (0.27-0.67)19.2 (15.0-25.9)0.41 (0.24-0.67)Placebo-combination354.7 (2.2-5.5)7.5 (4.6-10.0)Pts Without Brain MetastasesPembro-combination3379.2 (8.3-10.9)0.48 (0.39-0.59)22.4 (19.7-25.4)0.59 (0.46-0.75)Placebo-combination1714.9 (4.7-5.9)12.1 (9.1-15.0)*25 patients had both brain and liver metastases. 1 of 2 Citation Format: Marina C. Garassino, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Giovanna Speranza, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J. Hochmair, Steven F. Powell, Susanna Y.-S. Cheng, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E. Gray, Anna Cardellino, Jing Yang, M. Catherine Pietanza, Delvys Rodríguez-Abreu. Outcomes among patients (pts) with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab (pembro) plus pemetrexed-platinum: Results from the KEYNOTE-189 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT043.

Tislelizumab, an investigational anti-PD-1 antibody, combined with chemotherapy as first-line treatment for lung cancer in Chinese patients.

e14067 Background: Tislelizumab, an investigational anti-PD-1 antibody, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports showed tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors; 200 mg IV Q3W was established as the RP2D. Methods: This phase 2 clinical trial (NCT03432598) assessed tislelizumab (200 mg Q3W) with platinum (plt)-based chemotherapy (Q3W) as first-line treatment for Chinese pts with advanced lung cancer. All pts received tislelizumab + plt doublet (4–6 cycles) until disease progression. Nonsquamous (nsq) NSCLC pts received pemetrexed (PMX) + plt (4 cycles) followed by PMX maintenance; squamous (sq) NSCLC pts received A) paclitaxel (PXL) + plt or B) gemcitabine + plt; SCLC pts received etoposide + plt. Tumor response (RECIST v1.1) and safety/tolerability were evaluated. PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results: As of 15 Oct 2018, 54 pts (median age 61 yr; 74% male; 72% current/former smokers; 31% with ≥10% PD-L1 expression on tumor cells) received tislelizumab; 24 pts remain on treatment. Confirmed PR was observed in 36 pts and most occurred within the first 2 assessments. Other efficacy estimates (eg, PFS) are maturing. Grade ≥3 AEs occurring in &gt; 15% of pts were decreased neutrophil counts (n = 25) and anemia (n = 9); immune-related AEs occurring in ≥2 pts were decreased triiodothyronine, hyperthyroidism, hypothyroidism, and pyrexia (n = 2 each). One sq-NSCLC pt ( A) experienced fatal myocarditis/myositis after 1 cycle; other AEs resolved with tislelizumab interruption (n = 30), discontinuation (n = 4), or other appropriate treatment. Conclusions: Tislelizumab in combination with standard of care plt-based chemotherapy was generally well tolerated and demonstrated antitumor activity. Clinical trial information: NCT03432598. [Table: see text]

Randomized phase 2 study of maintenance pemetrexed (Pem) versus observation (Obs) for patients (pts) with malignant pleural mesothelioma (MPM) without progression after first-line chemotherapy: Cancer and Leukemia Group B (CALGB) 30901 (Alliance).

8517 Background: Standard front-line chemotherapy for advanced MPM is (Pem and a platinum; optimal treatment duration is unknown. We performed a randomized phase 2 trial (NCT01085630) to determine if continuation of single-agent Pem after 4-6 cycles of Pem-platinum would improve progression-free survival (PFS). Methods: Eligible pts had histologically confirmed unresectable MPM, and performance status (PS) 0-1. Pts with at least stable disease following 4-6 cycles of Pem-platinum were stratified by first-line regimen (cis- or carboplatin) and histology (epithelioid versus other) and randomized 1:1 to Obs or continuation of Pem until progression. The primary endpoint was PFS. We assumed that Obs produced a median (m) PFS of 3 months (mo) and Pem would yield a 100% improvement in mPFS to 6 mo; 60 eligible pts (30 per arm) were to be randomized. Results: 72 pts from 30 sites registered 12/10-6/16. The study closed early due to slow accrual once 53 pts were randomized; 49 eligible pts (22 Obs, 27 Pem) are included in the efficacy analysis. Pt characteristics (Obs/Pem): age: median (range) 70 (39-85)/70 (52-87); male 68%/78%; PS 0 27%/33%; epithelioid histology 77%/70%; first-line cisplatin 27%/26%. A median of 4 cycles of Pem (range 1-33) was delivered; 22% of pts required dose modification. mPFS was 3 mo on Obs and 3.4 mo on Pem (hazard ratio (HR) 0.99; 95% CI: 0.51-1.90; p=0.9733). Median overall survival (mOS) was 11.8 mo for Obs, and 16.3 mo for Pem (HR 0.86; 95% CI 0.44-1.71; p=0.6737). Toxicities ≥ grade 3 on Pem included anemia 8%, lymphopenia 8%, neutropenia 4%, and fatigue 4%; there were no grade 5 toxicities. A higher baseline level of serum mesothelin related peptide (SMRP) was associated with worse PFS (HR 1.861, p=0.049). Baseline osteopontin did not significantly affect PFS (p=0.3630). Conclusions: Although it was well tolerated, maintenance Pem following initial Pem/platinum doublet chemotherapy does not improve PFS in MPM patients. High baseline SMRP was associated with shorter PFS. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01085630.

Treatment patterns, duration and outcomes of pemetrexed maintenance therapy in patients with advanced NSCLC in a real-world setting

Objectives: In patients with non-squamous non-small-cell lung cancer (NSCLC), maintenance therapy regimens, including pemetrexed, have been shown to prolong overall survival (OS) and progression-free survival (PFS). The purpose of this study was to describe real-world maintenance use of pemetrexed and associated outcomes in patients with advanced NSCLC.Methods: This was a retrospective, observational study that used longitudinal, demographically and geographically diverse electronic health record data in the United States. Eligible patients were adults with advanced non-squamous NSCLC who had received maintenance treatment with pemetrexed monotherapy or pemetrexed plus bevacizumab. Descriptive statistics were used to describe the patient population and multivariable logistic regression was used to identify the factors associated with duration of maintenance therapy. Kaplan–Meier curves and Cox regression models were used for time-to-event analysis.Results: Patients receiving pemetrexed maintenance therapy were treated with either pemetrexed monotherapy (66.0%) or pemetrexed plus bevacizumab (34.0%). Carboplatin and pemetrexed (37.9%) or carboplatin, pemetrexed and bevacizumab (36.1%) were the most commonly used first-line therapies observed. The majority (84.9%) of these maintenance patients responded to first-line therapy. The median duration of maintenance therapy was 6.0 months for pemetrexed and bevacizumab and 4.1 months for pemetrexed monotherapy. The median OS from the start of first-line therapy of the total study cohort was 21.5 months (95% CI 20.0, 22.9).Conclusion: Real-world effectiveness of pemetrexed maintenance therapy is similar to that observed in published randomized controlled trials, confirming a role for pemetrexed maintenance in eligible patients in clinical practice.

Pemetrexed and carboplatin combination therapy followed by pemetrexed maintenance in Japanese patients with non-squamous non-small cell lung cancer: A subgroup analysis of elderly patients.

The combination of pemetrexed and carboplatin is commonly used for the treatment of advanced non-squamous non-small cell lung cancer (NSCLC), mainly because it is comparatively effective and less toxic than other platinum-doublet therapies. Using the JMII (JACAL) study, we report the efficacy and safety of this treatment followed by pemetrexed maintenance in the elderly population (≥70 years of age). The JMII study was a multicenter, post-marketing study that assessed the efficacy and safety of carboplatin (AUC6) and pemetrexed (500 mg/m2, given on Day 1 of a 21-day cycle, 4 cycles) followed by pemetrexed (500 mg/m2) maintenance in advanced non-squamous NSCLC patients (n = 109). Retrospective subgroup analyses were performed in elderly patients aged ≥70. The study includes younger (<70 years, n = 84) and elderly (≥70 years, n = 25) patients who received induction therapy. Median progression-free survival and overall survival from the start of the induction phase were 5.2 (95% CI: 3.5, 8.2) and 16.8 (95% CI: 10.3, NC) months for the elderly patients compared with 5.8 (95% CI: 4.3, 7.4) and 20.5 (95% CI: 16.7, NC) months for the younger patients, respectively. Grade 3/4 hematologic toxicities were more frequent in the elderly patients. Non-hematologic toxicities in the elderly patients were comparable to those in younger patients. Dose reduction was more common in the elderly (44% vs 23%), due to hematologic toxicities. There was no difference in efficacy (evaluated by progression-free survival) between elderly and younger patients. Although grade 3/4 hematologic toxicities were frequently observed in the elderly patients, they were easily managed with dose adjustment.

P1.15-36 A Better Real World Practice for Pemetrexed in First-Line Treatment of Advanced Mon-Squamous Non-Small Cell Lung Cancer

To investigate the real world practice of first-line pemetrexed combined with different drugs in patients with advanced Non-squamous non-small cell lung cancer. A total number of 164 patients from February 2012 to August 2017 in Hunan Cancer Hospital in the combination of pemetrexed with cisplatin were enrolled in this study. All the patients were divided into 5 groups: PC-P (pemetrexed combined with platinum for 4 cycles and pemetrexed maintenance, arm A), PCA-PA (Pemetrexed plus platinum and bevacizumab 4cycles, pemetrexed combined with bevacizumab maintenance, arm B), PC (pemetrexed combined with platinum chemotherapy 4 cycles, arm C), PCA (pemetrexed with platinum chemotherapy, plus bevacizumab 4 cycles without maintenance, arm D), PC-EGFR TKI (pemetrexed plus platinum chemotherapy 4 cycles, and then EGFR TKI as maintenance treatment, arm E). Efficacy and safety of pemetrexed was performed in each group comparing with each major clinical data. According to retrospective study , the median PFS for arm A, B, C, D and E were 13 months, 12 months, 5 months, 5 months, 15.8 months respectively; the median OS was 27 month, 21 months, 15 months, 11 months and 31 months respectively. Arm A and Arm C, Arm B and Arm D achieved statistically different on PFS (p<0.05). And Arm A and Arm C, Arm B and Arm D also achieved statistical differences between OS (p<0.05). In the multivariate regression analysis of all patients, we found that the ECOG PS score may be an independent prognostic factor for death from lung cancer patients. Among all the patients, 35 (21.4%) patients presented with non-hematologic serious adverse event (grade 3 and 4). There was no new occurring intolerant adverse event comparing with other clinical trials. In this real world study, pemetrexed proved to be high efficacy and well tolerant in advanced NSCLC. The efficiency of maintenance pemetrexed treatment group achieved significantly better outcome than the non-maintenance treatment group. In addition, ECOG PS score may be an independent prognostic factor for the death of patients in lung cancer. There was no new occurring intolerant adverse event comparing with previous clinical trials, the main adverse events in this study were also focused on non-hematologic toxicity. This is consistent with clinical trials.

BEVACIZUMAB-INDUCED BRONCHIAL PERFORATION

SESSION TITLE: Lung Cancer SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Bevacizumab is a recombinant IgG1 antibody to VEGF currently approved for use in advanced non-small cell lung cancer. Phase III trials have demonstrated that bevacizumab addition to antineoplastic regimens have improved survival in this patient population. Bevacizumab causes microvascular involution in tumors and suppression of tumor angiogenesis. There are many recorded sinopulmonary toxicities such as pulmonary hemorrhage, venous thromboembolism, and nasal septal perforation. Here we report bronchial perforation in the setting of advanced pulmonary adenocarcinoma. CASE PRESENTATION: Our patient is a 56 year old male with a 30 pack-year smoking history who initially presented to the pulmonary clinic with wheezing, cough and shortness of breath. Imaging at the time showed a right supra hilar mass and right upper lobe collapse. Bronchoscopy with endobronchial ultrasound (EBUS) was performed with subsequent pathology showing poorly differentiated adenocarcinoma (EGFR negative, ALK-EML4 negative, ROS1 negative); left adrenal biopsy confirmed metastasis. His treatment consisted of cisplatin and pemetrexed every three weeks for four total cycles with complete adrenal and partial pulmonary response. Following this treatment, he underwent six weeks of low dose carboplatin and paclitaxel with concurrent thoracic radiation, followed by three weeks of maintenance pemetrexed. He suffered from recurrent post-obstructive pneumonias due to his chronic RUL obstruction and the obstruction unfortunately was not amenable to endobronchial intervention. He also developed pneumonitis after multiple rounds of radiation and a right-sided para malignant pleural effusion. Video-assisted thoracoscopic surgery and indwelling pleural catheter placement by thoracic surgery was performed. Carboplatin and paclitaxel with the addition of bevacizumab every three weeks for six cycles was then started followed by maintenance bevacizumab. He presented with hemoptysis 15 months after starting bevacizumab. Bronchoscopy was performed, revealing loss of the integrity of the bronchial wall of the right bronchus intermedius with tissue protruding through the bronchial wall. It was recommended at that time to discontinue bevacizumab DISCUSSION: To our knowledge, this is the only case in the current literature of bronchial perforation secondary to bevacizumab. Literature review predominantly revealed nasal perforation as the most common sinopulmonary complication from bevacizumab treatment with pulmonary hemorrhage being a close second. In our case, the patient was on bevacizumab 15 mg/kg every 3 weeks for 6 total cycles and then maintenance dose for 37 total cycles (15 total months). His treatment had to be stopped given the extent of the perforation. CONCLUSIONS: Bevacizumab toxicity is well reported in the upper airway. Our case is one of pulmonary involvement most likely due to a vascular mediated effect causing airway necrosis Reference #1: Keating, Gillian M. “Bevacizumab: A Review of Its Use in Advanced Cancer.” Drugs, vol. 74, no. 16, 2014, pp. 1891–1925. Reference #2: Higa, Gerald M, and Jame Abraham. “Biological Mechanisms of Bevacizumab-Associated Adverse Events.” Expert Review of Anticancer Therapy, vol. 9, no. 7, 2009, pp. 999–1007. Reference #3: Vahid, Bobbak, and Paul E. Marik. “Pulmonary Complications of Novel Antineoplastic Agents for Solid Tumors.” Chest, vol. 133, no. 2, 2008, pp. 528–538. DISCLOSURES: No relevant relationships by Chhaya Patel, source=Web Response No relevant relationships by Juan Sanchez, source=Web Response

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer

IntroductionCohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis. MethodsA total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025). ResultsAs of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. ConclusionsThe significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC.

Long-term survival follow-up of atezolizumab in combination with platinum-based doublet chemotherapy in patients with advanced non–small-cell lung cancer

BackgroundBefore the availability of immunotherapy, chemotherapy was standard first-line therapy for non–small-cell lung cancer (NSCLC) lacking actionable gene alterations. Preclinical evidence suggests chemotherapy is immunomodulatory, supporting chemotherapy/immunotherapy combinations. Atezolizumab, anti-programmed death ligand-1 (PD-L1) antibody, blocks programmed cell death protein-1 and B7.1 interaction with PD-L1. GP28328 (NCT01633970) assessed atezolizumab with chemotherapy in multiple tumours; we report results for advanced, treatment-naïve NSCLC. MethodsPatients received atezolizumab plus carboplatin with paclitaxel (Arm C: atezo/cb/pac), pemetrexed (Arm D: atezo/cb/pem, maintenance pemetrexed permitted), or nab-paclitaxel (Arm E: atezo/cb/nab-pac), four–six cycles, then atezolizumab maintenance. Primary end-point was safety; secondary end-points were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). ResultsSeventy-six NSCLC patients were enrolled (n = 25, 25 and 26 for Arms C, D and E, respectively). Common treatment-related grade III/IV adverse events were neutropenia (36% atezo/cb/pac, 36% atezo/cb/pem, 42% atezo/cb/nab-pac) and anaemia (16% atezo/cb/pac, 16% atezo/cb/pem, 31% atezo/cb/nab-pac). Confirmed ORRs were 36% atezo/cb/pac, 68% atezo/cb/pem (one complete response [CR]) and 46% atezo/cb/nab-pac (four CRs). Median PFS was 7.1 months, (95% confidence interval [CI]: 4.2–8.3), 8.4 months (95% CI: 4.7–11) and 5.7 months (95% CI: 4.4–14.8), respectively. Median OS was 12.9 months (95% CI: 8.8–21.3), 18.9 months (95% CI: 9.9–27.4) and 17.0 months (95% CI: 12.7–not evaluable), respectively. ConclusionAtezolizumab with chemotherapy was well tolerated with encouraging efficacy, though the analysis was limited by small numbers. NSCLC chemotherapy combination studies are ongoing. ClinicalTrials.gov identifierNCT01633970.