Metastatic Nonsquamous NSCLC Research Articles

Exceptional pemetrexed sensitivity can predict therapeutic benefit from subsequent chemotherapy in metastatic non-squamous non-small cell lung cancer.

Based on an exceptionally durable response to pemetrexed observed in some patients with metastatic NSCLC, the predictive value of pemetrexed sensitivity to outcomes of subsequent systemic treatment was investigated. We retrospectively reviewed the patients with metastatic non-squamous NSCLC treated with pemetrexed monotherapy as their first- or second-line chemotherapy between November 2006 and February 2015. Good (top 5% longest) and poor responders (bottom 12% shortest) were defined according to the duration of pemetrexed maintenance. The first and second post-pemetrexed (PP) systemic treatments were defined as PP1 and PP2 therapies, respectively, to define their progression-free survivals (PFS) as PFS1 and PFS2. In a total of 100 patients, 86% of patients received pemetrexed as their second-line chemotherapy, and 34% were classified as good responders. Good and poor responder groups showed 20.5months and 0.7months of the median duration of responses, respectively. PP1 and PP2 therapies were done in 74% and 41.9% of patients after failure to pemetrexed. To our surprise, disease control rate (DCR) was significantly higher in the good responder group than poor responder group (69.6% vs 37.3%, p = 0.010) in patients treated with PP1 therapy, and median PFS1 was also significantly longer (5.2vs2.2 months, p < 0.01) regardless of the type of subsequent systemic treatment. Meanwhile, pemetrexed sensitivity did not affect DCR or PFS of patients who received PP2 therapies. Patients who achieved durable response to pemetrexed might obtain greater therapeutic benefits from subsequent systemic treatment in metastatic non-squamous NSCLC without targets, which could potentiate more effective post-pemetrexed treatment strategy.

KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC.

9013 Background: Pembro + chemo significantly improved OS and PFS over chemo alone and had manageable safety as 1L therapy for metastatic nonsquamous NSCLC in the KEYNOTE-189 study (NCT02578680). The benefit was observed irrespective of PD-L1 TPS. We present updated OS based on longer follow-up and, for the first time, PFS2. Methods: Eligible pts were randomized 2:1 to pembro (n = 410) or placebo (n = 206) + pemetrexed and carboplatin or cisplatin for 4 cycles followed by pembro or placebo for up to 35 cycles + maintenance pemetrexed. Pts in the chemo arm could crossover to pembro alone upon PD. Poststudy anticancer therapy and outcomes were collected. PFS2 was defined as time from randomization to PD per investigator after start of 2L therapy or death, whichever occurred first. There was no multiplicity adjustment, and all P values are nominal. Data cutoff was 21 Sep 2018. Results: With 18.7-mo median follow-up, pembro + chemo continued to provide longer OS (HR 0.56 [95% CI 0.45-0.70], P &lt; .00001; median 22.0 mo vs 10.7 mo) and PFS (HR 0.48 [95% CI 0.40-0.58], P &lt; .00001). Benefit was seen in all PD-L1 TPS groups (Table). 2L+ therapy was received by 45% in the pembro + chemo arm and 59% (54% 2L+ immunotherapy) in the placebo + chemo arm. PFS2 was longer for 1L pembro + chemo (HR 0.49 [95% CI 0.40-0.59], P &lt; .00001; median 17.0 mo vs 9.0 mo), with no difference by TPS (Table). Conclusions: 1L pembro + pemetrexed/platinum continued to show substantial OS benefit in metastatic nonsquamous NSCLC, regardless of PD-L1 TPS and despite 54% of pts in the placebo + chemo arm receiving subsequent immunotherapy. Median OS, PFS and PFS2 were approximately doubled with pembro + chemo. These data confirm that pembro should be given as part of 1L therapy to maximize outcomes in both PD-L1–expressing and PD-L1–non-expressing NSCLC. Clinical trial information: NCT02578680. [Table: see text]

148P - KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic non-squamous NSCLC

148P - KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic non-squamous NSCLC

FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC

FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC

532P - KEYNOTE-189 study of pembrolizumab (pembro) plus pemetrexed (pem) and platinum vs placebo plus pem and platinum for untreated, metastatic, nonsquamous NSCLC: Does choice of platinum affect outcomes?

Background: In KEYNOTE-189 (NCT02578680), pembro plus pem and platinum provided superior OS (HR 0.49, P < 0.00001) and PFS (HR 0.52, P < 0.00001) and had manageable safety vs placebo plus pem and platinum as first-line therapy for metastatic nonsquamous NSCLC. In an exploratory analysis, we assessed outcomes by investigator’s choice of carboplatin (carbo) or cisplatin (cis). Methods: 616 patients (pts) with untreated metastatic nonsquamous NSCLC regardless of PD-L1 TPS without sensitizing EGFR or ALK alteration were randomized 2:1 to 4 Q3W cycles of pembro 200 mg or placebo + pem 500 mg/m2 + carbo AUC 5 or cis 75 mg/m2 followed by maintenance pembro or placebo + pem. Randomization was stratified by TPS (<1% vs ≥ 1%), platinum (carbo vs cis), and smoking status (current/former vs never). Primary end points were OS and PFS; ORR and safety were secondary. Results: Carbo was chosen for 72% of pts in both arms. OS, PFS, and ORR were improved in the pembro plus pem and platinum arm in both carbo and cis recipients (Table). In the pembro vs placebo arm, 83% vs 72% received 4 carbo doses and 81% vs 79% received 4 cis doses. 76% vs 65% and 78% vs 72%, respectively, received ≥5 pem doses. Grade 3-5 AE rates for pembro vs placebo were 70% vs 66% with carbo and 59% vs 65% with cis. Rates of the most common any-grade AEs were generally similar for carbo and cis: nausea 54% with pembro vs 48% with placebo for carbo and 60% vs 63% for cis, anemia 45% vs 48% and 50% vs 44%, and fatigue 44% vs 43% and 33% vs 26%. Rates of acute kidney injury in the pembro arm were 5.1% with carbo and 5.4Table532PCarboCisPembro + Chemo N = 297Placebo + Chemo N = 148Pembro + Chemo N = 113Placebo + Chemo N = 58OS, medianNR (NR-NR)11.3 (8.0-NR)NR (NR-NR)10.8 (8.1-NR)(95% CI), moHR (95% CI)0.52 (0.39-0.71)0.41 (0.24-0.69)PFS, median8.6 (7.1-9.2)4.9 (4.6-5.6)9.2 (6.9-11.1)4.8 (4.7-6.0)(95% CI), moHR (95% CI)0.55 (0.44-0.70)0.44 (0.30-0.65)ORR, % (95% CI)47 (41-53)18 (12-25)49 (39-58)21 (11-33) Open table in a new tab % with cis. Conclusions: Pembro plus pem and platinum improved efficacy and was generally tolerable compared with placebo plus pem and platinum regardless of the chosen platinum. These data support the use of both carbo and cis in combination with pembro and pem as first-line therapy for metastatic nonsquamous NSCLC. Editorial acknowledgement: Sheri Arndt. Clinical trial identification: MK-3475-189, NCT02578680. Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding: Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure: M.C. Garassino: Personal fees as a consultant, advisor: AZ, BI, BMS, Lilly, MSD, Roche; Travel support: Lilly, MSD, Pfizer; Research funding to the institution: AZ, AZ/MedImmune, BMS, MSD, Roche/Genentech. E. Felip: Personal fees as a consultant, advisor: AZ, BMS, BI, Celgene, Guardant Health, Lilly, MSD, Novartis, Pfizer, Roche,Takeda; Speaker: AZ, BI, BMS, MSD, Novartis, Pfizer, and Roche. S. Powell: Personal fees as a consultant, advisor: BMS; Research funding to the institution: BMS, Genentech/Roche, Incyte, MSD, Novartis, Pfizer,Vyriad. S.Y-S. Cheng: Personal fees as a consultant, advisor: Merck, Roche. N. Peled: Grants, personal fees, honoraria for serving as an advisor: AZ, BI, BMS, Lilly, MSD, Novartis, Pfizer, Roche, NovellusDx, FMI, Gaurdant360. R. Hui: Advisor: MSD, AZ, Roche, BMS,Novartis; Speaker honoraria: MSD, Novartis, AZ, Roche, BMS. M. Reck: Personal fees for lectures, consultant: Roche, Lilly, AZ, BI, BMS, Celgene, MSD, Merck, Novartis, Pfizer, AbbVie. E.B. Garon: Institution research funding: AZ, BI, BMS, Genentech, Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer. M. Boyer: Travel funds: BI, BMS, Genentech/Roche (G/R),MSD; To institution: AZ, BMS, MSD, Amgen, Ascentage Pharma, BeiGene, BI, G/R, Lilly, OncoMed, Peregrine Pharmaceuticals, Pfizer. F. Grossi: Personal fees for serving as a consultant, advisor, lectures: MSD, BMS, AstraZeneca, Pierre Fabre, Roche, Pfizer; Research funding: BMS. J. Yang, M.C. Pietanza: Full-time employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. S. Gadgeel: Personal fees: Ariad, AZ, BMS, Genentech/Roche (G/R), Pfizer, Takeda; To Institution: ACEA Biosciences, Acerta, AZ, BMS, Five Prime Therapeutics, G/R, Halozyme, Incyte, Janssen Oncology, Merck, Millennium, Novartis, OncoMed, Pfizer. All other authors have declared no conflicts of interest.

P1.01-104 Updated Phase I Results of Carboplatin, Pemetrexed and Exemestane in Postmenopausal Women with Metastatic Non-Squamous NSCLC

P1.01-104 Updated Phase I Results of Carboplatin, Pemetrexed and Exemestane in Postmenopausal Women with Metastatic Non-Squamous NSCLC

P3.01-09 Impact of Urban or Rural Residence on Overall Survival for Patients with Metastatic Non-Squamous NSCLC

P3.01-09 Impact of Urban or Rural Residence on Overall Survival for Patients with Metastatic Non-Squamous NSCLC

P1.01-52 BR-34- Randomized Trial of Durvalumab and Tremelimumab +/- Platinum Chemotherapy in Patients with Metastatic Squamous or Non-Squamous NSCLC

P1.01-52 BR-34- Randomized Trial of Durvalumab and Tremelimumab +/- Platinum Chemotherapy in Patients with Metastatic Squamous or Non-Squamous NSCLC

Cost-effectiveness of pembrolizumab in combination with chemotherapy in the 1st line treatment of non-squamous NSCLC in the US

Aims: To describe cost-effectiveness of pembrolizumab plus platinum and pemetrexed chemotherapy in metastatic, non-squamous, NSCLC patients in the US.Materials and methods: A model is developed utilizing partitioned survival analysis to estimate the cost-effectiveness of KEYNOTE-189 trial comparators pembrolizumab + chemotherapy (carboplatin/cisplatin + pemetrexed) vs chemotherapy alone. Clinical efficacy, treatment utilization, health utility, and safety data are derived from the trial and projected over 20 years. For extrapolating survival beyond the trial, a novel SEER population-data approach is applied (primary analysis), with separate estimation via traditional parametric extrapolation methods. Costs for drugs and non-drug disease management are also incorporated. Based on an indirect treatment comparison, cost-effectiveness of pembrolizumab + chemotherapy vs pembrolizumab monotherapy is evaluated for patients with programmed death-ligand 1 (PD-L1) ≥ 50%.Results: In the full non-squamous population, pembrolizumab + chemotherapy is projected to increase life expectancy by 2.04 years vs chemotherapy (3.96 vs 1.92), for an approximate doubling of life years. Resultant incremental cost-effectiveness ratios (ICERs) are $104,823/QALY and $87,242/life year. In patients with PD-L1 ≥ 50% and 1–49%, life expectancy is more than doubled (4.53 vs 1.88 years) and (4.87 vs 2.01 years), with a 32% (2.60 vs 1.97 years) increase in PD-L1 < 1% patients. Corresponding incremental costs/quality-adjusted life year (QALY) are $103,402, $66,837, and $183,529 for PD-L1 ≥ 50%, 1–49%, and <1% groups, respectively. Versus pembrolizumab monotherapy in PD-L1 ≥ 50% patients, representing current standard of care, pembrolizumab + chemotherapy increases life expectancy by 65% (4.53 vs 2.74 years) at an ICER of $147,365/QALY.Limitations and conclusions: The addition of pembrolizumab to chemotherapy is projected to extend life expectancy to a point not previously seen in previously untreated metastatic non-squamous NSCLC. Although ICERs vary by sub-group and comparator, results suggest pembrolizumab + chemotherapy yields ICERs near, or in most cases, well below a 3-times US per capita GDP threshold of $180,000/QALY, and may be a cost-effective first-line treatment for metastatic non-squamous NSCLC patients.

FDA grants regular approval for pembrolizumab in combination with chemotherapy for first-line treatment of metastatic nonsquamous NSCLC

FDA grants regular approval for pembrolizumab in combination with chemotherapy for first-line treatment of metastatic nonsquamous NSCLC

Abstract CT075: KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC

Abstract Background: The premise that chemotherapy and immunotherapy may provide greater benefit than pembro or chemotherapy alone was supported by KEYNOTE-021 cohort G, in which pembro + pem + carboplatin significantly improved ORR and PFS over pem + carboplatin in patients (pts) with advanced nonsquamous NSCLC. We present results of the KEYNOTE-189 study of pembro + pem-platinum vs placebo + pem-platinum as first-line therapy for metastatic nonsquamous NSCLC. Methods: Pts with previously untreated stage IV nonsquamous NSCLC, no EGFR or ALK alteration, and ECOG PS 0-1 were randomized 2:1 to 4 Q3W cycles of pembro 200 mg or placebo + pem 500 mg/m2 + carboplatin AUC 5 or cisplatin 75 mg/m2 followed by maintenance pembro or placebo + pem. Randomization was stratified by PD-L1 tumor proportion score (TPS; &amp;lt;1% vs ≥1%), platinum agent, and smoking status. Response was assessed by RECIST v1.1 per blinded, independent central review. Pts in the placebo arm with verified PD could crossover to pembro monotherapy if eligible. Primary end points were OS and PFS in the ITT population. Prespecified superiority boundaries at the first interim analysis were one-sided P = .00128 for OS and .00559 for PFS. Results: 616 pts were randomized: 410 to pembro + pem + platinum (“pembro arm”), 206 to placebo + pem + platinum (“placebo arm”). 76.5% of treated pts in the pembro arm and 66.8% in the placebo arm received ≥5 cycles of pem. 88.1% of enrolled pts were current/former smokers, carboplatin was chosen for 72.2%, and 63.0% had TPS ≥1%. As of Nov 8, 2017, median follow-up was 10.5 mo (range 0.2-20.4), and 33.8% in the pembro arm vs 17.8% in the placebo arm remained on treatment. In the placebo arm, 67 pts crossed over in-study to pembro and 18 received anti-PD-(L)1 therapy outside the study (effective crossover rate: 41.3% in the ITT population, 50.0% when pts still on treatment excluded). Pembro + pem + platinum, improved OS (HR 0.49; 95% CI 0.38-0.64; P &amp;lt; .00001) and PFS (HR 0.52; 95% CI 0.43-0.64; P &amp;lt; .00001) over placebo + pem + platinum. Median OS was not reached with pembro and was 11.3 mo with placebo. Median PFS was 8.8 mo vs 4.9 mo. OS benefit in the pembro arm was observed across subgroups, including all PD-L1 TPS categories (HR [95% CI] 0.59 [0.38-0.92] for &amp;lt;1%, 0.55 [0.34-0.90] for 1-49%, and 0.42 [0.26-0.68] for ≥50%). ORR was higher with pembro (47.6% vs 18.9%; P &amp;lt; .00001). Grade ≥3 AEs occurred in 67.2% of pts in the pembro arm vs 65.8% in the placebo arm; AEs led to discontinuation of any treatment in 27.7% vs 14.9%, all treatment in 13.8% vs 7.9%, and death in 6.7% vs 5.9%. Conclusions: Pembro + pem + platinum provided superior OS, PFS, and ORR compared with placebo + pem + platinum and had a manageable safety profile in pts with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK alterations. These data suggest first-line pembro + pem and platinum may be a new standard of care for this population. Citation Format: Leena Gandhi, Delvys Rodgríguez-Abreu, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J Hochmair, Steven Powell, Susanna Yee-Shan 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, John J Vida, Ziwen Wei, Jing Yang, Harry Raftopoulos, M. Catherine Pietanza, Marina C Garassino. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT075.

Abstract CT076: IMpower150: Efficacy of atezolizumab (atezo) plus bevacizumab (bev) and chemotherapy (chemo) in 1L metastatic nonsquamous NSCLC (mNSCLC) across key subgroups

Abstract Introduction: Atezo (anti-PD-L1) + bev + chemo prolonged PFS vs bev + chemo in patients (pts) with 1L non-squamous mNSCLC in the randomized Ph 3 IMpower150 study regardless of PD-L1 expression. This analysis aims to further understand the efficacy of atezo + bev + chemo in key subgroups: PD-L1 expression subgroups defined by the SP142 and SP263 IHC assays, patients with EGFR/ALK genetic alterations and patients with liver metastases at baseline. Methods: Pts received atezo 1200 mg + bev 15 mg/kg + carboplatin (C) AUC 6 + paclitaxel (P) 200 mg/m2 (Arm B) or bev + C + P (Arm C) IV q3w. A co-primary endpoint (EP) was PFS in the ITT-WT (EGFR or ALK wild-type pts); a secondary EP was PFS in subgroups defined by PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) with SP142. Retrospective analysis with SP263 was a prespecified exploratory EP. Results: In Arms B and C of the ITT-WT (n = 692), 503 pts had available tumor sections for SP263 testing (BEP). Pt characteristics in the ITT-WT and BEP were similar. A similar PFS benefit was observed for Arm B vs C across all PD-L1 expression subgroups defined by either assay, including pts with PD-L1-negative and PD-L1-low tumors (Table). PFS benefit with Arm B vs C was also observed in patients with EGFR or ALK genomic alterations, including patients with actionable EGFR mutations, and in patients with liver metastases at baseline (Table). Conclusion: PFS benefit with atezo + bev + chemo was observed across all PD-L1 subgroups, regardless of the IHC assay used. Additionally, clinically meaningful PFS benefit was observed in patients with EGFR/ALK genomic alterations, and in patients with liver metastases with this combination. Table. PFS in Biomarker Subgroups and Other Subgroups of Interest in IMpower150Median PFS, moPFSan (%)HRb (95% CI)P ValueArm BArm CITT-WT692 (100%)0.62 (0.52, 0.74)&amp;lt;0.00018.36.8BEP with SP263 results in ITT-WT503 (73%)0.62 (0.50, 0.76)&amp;lt;0.00018.36.8PD-L1 Expression Subgroups Defined by the VENTANA SP142 Assay (BEP, n=503)PD-L1 negative TC0 and IC0235 (47%)0.77 (0.57, 1.04)0.08368.27.0PD-L1 low TC1/2 or IC1/2167 (33%)0.53 (0.37, 0.76)0.00058.36.1PD-L1 high TC3 or IC3101 (20%)0.49 (0.30, 0.79)0.003211.16.9PD-L1 Expression Subgroups Defined by the VENTANA SP263 IHC Assay (BEP, n=503)PD-L1 negative TC &amp;lt; 1%237 (47%)0.72 (0.53, 0.97)0.02987.27.0PD-L1 low TC &amp;lt; 50% and ≥ 1%140 (28%)0.57 (0.38, 0.84)0.00419.76.9PD-L1 high TC ≥ 50%126 (25%)0.50 (0.33, 0.77)0.00159.16.2Other Subgroups of Interest (ITT, n=800)ITT800 (100%)0.61 (0.52, 0.72)&amp;lt;0.00018.36.8EGFR/ALK+c108 (14%)0.59 (0.37, 0.94)0.02539.76.1EGFR exon 19 deletion of L858R59 (7%)0.41 (0.22, 0.78)0.005010.26.1Liver metastases110 (14%)0.40 (0.26, 0.62)&amp;lt;0.00018.25.4No liver metastases690 (86%)0.64 (0.53, 0.76)&amp;lt;0.00018.37.0BEP, biomarker-evaluable population; IC, tumor-infiltrating immune cell; IHC, immunohistochemistry; PD-L1, programmed death-ligand 1; TC, tumor cell; WT, wild type. TC0 and IC0 = PD-L1 expression on &amp;lt; 1% of TC or IC; TC1/2 or IC1/2 = PD-L1 expression on &amp;lt; 50% and ≥ 1% of TC or &amp;lt; 10% of and ≥ 1% of IC; TC3 or IC3 = PD-L1 expression on ≥ 50% of TC or ≥ 10% of IC. a Investigator assessed b Stratified HR for ITT-WT and ITT; unstratified HR for all other subgroups. c Patients with a sensitizing EGFR mutation or ALK rearrangement must have disease progression or intolerance of treatment with one or more approved targeted therapies. d Other EGFR mutations include L861Q, G719X, S7681, exon 20 insertion, T790M, and other. (NCT02366143) Citation Format: Marcin Kowanetz, Mark A. Socinski, Wei Zou, Mark McCleland, Nancy Yang, Ariel Lopez Chavez, Alexander Spira, Julien Mazières, Fadi Braiteh, David Shames, Alan Sandler, Martin Reck. IMpower150: Efficacy of atezolizumab (atezo) plus bevacizumab (bev) and chemotherapy (chemo) in 1L metastatic nonsquamous NSCLC (mNSCLC) across key subgroups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT076.

Pericardial Effusion with Tamponade, an Immune-Related Adverse Event Associated with Nivolumab Therapy: A Case Report and Review of the Literature

Immune checkpoint inhibitors have shown to be very effective when treating lung cancer. Nivolumab, a programmed death-1 (PD-1) inhibitor has been approved for the treatment of metastatic non-squamous and squamous NSCLC. Immunotherapy with checkpoint inhibitors are associated with toxicities defined as immune-related adverse events (irAEs). The most common irAEs are rash, colitis, hepatitis, pneumonitis, and endocrinopathies. Although any organ system can be affected, other rare irAEs can occur and affect the bone marrow, pancreas, and the neurologic and cardiac systems. Pericardial effusion induced by immunotherapy is uncommon and has been described only in a few case reports. Immune-related adverse events usually develop within the first weeks to months after treatment initiation. This is a case report of a 52-year-old male patient with metastatic squamous-cell lung cancer who had a massive pericardial effusion secondary to treatment with nivolumab as second line treatment. During his hospital stay, the patient underwent pericardiocentesis and treatment with corticosteroids. A CT scan after these treatments revealed complete tumor response and minimal pericardial effusion. Nivolumab was definitively ceased. The patient continues to show complete response for 16 months. In general, Nivolumab is well-tolerated and has an excellent safety profile. However, it is important to be aware of life-threatening immune-related adverse events, particularly cardiac toxicity. Consensus guidelines regarding the treatment of the most common irAEs have been established. The optimal management of irAEs is based on clinical experience. It’s crucial to report new or rare irAEs to conduct prospective trials to evaluate the best treatment strategy.

P2.01-020 Continuous Intravenous Infusion Endostar Combined with Pemetrexed plus Cisplatin in Chinese Treatment-Naïve Metastatic Non-Squamous NSCLC

P2.01-020 Continuous Intravenous Infusion Endostar Combined with Pemetrexed plus Cisplatin in Chinese Treatment-Naïve Metastatic Non-Squamous NSCLC

MS 05.04 Practical Approach to Combination of Chemotherapy with IO

Combination of chemotherapy with immune-check point inhibitor is considered to be one of the most promising strategy to improve efficacy of immune-check point inhibitors. Several clinical trials of chemotherapy with immune-check point inhibitor are conducted and the results have been reported. KEYNOTE-021 cohort G is a randomized, open-label, phase 2 cohort of a multi-cohort study assessed whether the addition of pembrolizumab to carboplatin and pemetrexed improves efficacy in patients with advanced non-squamous NSCLC. Thirty-three (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (p=0·0016). Progression-free survival (PFS) was significantly longer with pembrolizumab plus chemotherapy compared with chemotherapy alone (HR 0·53 [95% CI 0·31–0·91]; p=0·010). Median PFS was 13·0 months for pembrolizumab plus chemotherapy and 8·9 months for chemotherapy alone. The FDA has granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced non-squamous NSCLC, regardless of PD-L1 expression. Antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab that are currently approved for use in the treatment of NSCLC. Bevacizumab, in addition to platinum-based chemotherapy is widely used for the first-line treatment of advanced, metastatic, or recurrent NSCLC, excluding squamous cell carcinoma. VEGF influences lymphocyte trafficking across endothelia to the tumor by inhibiting lymphocyte adhesion and VEGF has a systemic effect on immune-regulatory cell function through multiple mechanisms, such as Tregulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs); suppression of dendritic cell maturation; and inhibition of T-cell development from hematopoietic progenitor cells. Thus, combination of antiangiogenic monoclonal antibody and immune-check point inhibitor is potentially synergistic. National Cancer Center Hospital conducted a single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced NSCLC. In this trial, nivolumab with gemcitabine/cisplatin, pemetrexed/cisplatin, paclitaxel/carboplatin/bevacizumab, or docetaxel were evaluated for six patients each arm. Combination of nivolumab and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Although small number of patients, nivolumab with paclitaxel/carboplatin/bevacizumab seems to be most promising with higher response rate and longer PFS. Based on these data, phase III study of paclitaxel/carboplatin/bevacizumab with/without nivolumab for advanced non-squamous NSCLC is ongoing. antiangiogenic monoclonal antibody, chemotherapy, immune-check point inhibitor

Abstract 560: Retrospective evaluation, of the randomized Phase 3 MARQUEE trial of tivantinib (T) + erlotinib (E) versus placebo (P) + erlotinib (E) using VeriStrat in patients with previously treated nonsquamous NSCLC

Abstract Background: MET, the high-affinity receptor for hepatocyte growth factor, is frequently deregulated in human cancer and is thought to be involved in resistance to EGFR TKIs. Tivantinib is an orally administered MET inhibitor currently under development as a cancer therapy. The Phase 3 MARQUEE trial enrolled 1048 subjects with locally-advanced or metastatic non-squamous NSCLC who had received one or two lines of prior systemic therapy. Patients were randomized 1:1 to T+E (N = 526) or P+E (N = 522) until disease progression. In the ITT population, addition of tivantinib to erlotinib significantly improved PFS and ORR but did not improve OS, the primary endpoint. VeriStrat® (VS) is a multivariate serum protein test that utilizes MALDI-TOF mass spectrometry to assign a “GOOD” (VS-G) or “POOR” (VS-P) classification and has demonstrated broad prognostic and predictive utility for EGFR TKI treatment regimens. Methods: Pre-treatment serum samples from the MARQUEE study were blinded to clinical outcome and analyzed by VeriStrat. Clinical benefit of T+E vs. P+E was analyzed as a function of VS status, in the ITT population as well as in pre-defined subgroups. Results: A total of 996 subjects were classified: 718 as VS-G and 278 as VS-P. Subjects testing VS-G had superior outcomes to those testing VS-P in both the T+E arm (OS HR = 0.32, CI: 0.26-0.41, p&amp;lt;0.0001; PFS HR = 0.55, CI: 0.44-0.69, p&amp;lt;0.0001) and P+E arm (OS HR = 0.43, CI: 0.34-0.55, p&amp;lt;0.0001; PFS HR = 0.70, CI: 0.55-0.88, p&amp;lt;0.028). VeriStrat status was a significant, independent predictor of OS, in these erlotinib treated patients, after adjustment for EGFR mutation, KRAS mutation, or MET IHC status. However, VeriStrat did not predict OS or PFS benefit for T+E vs. P+E (treatment * VS interaction p-value for OS of p = 0.09 and PFS of p = 0.19). VS was neither predictive nor prognostic for tivantinib effect in any molecular subgroup. Conclusion: These data support the previously demonstrated ability of VS to be both prognostic and predictive for survival in erlotinib treated patients, but not for tivantinib treated patients. Citation Format: Giorgio Scagliotti, Wallace Akerley, Joachim von Pawel, Joanna Roder, Dale Shuster, Brian Schwartz, Dominic Spinella. Retrospective evaluation, of the randomized Phase 3 MARQUEE trial of tivantinib (T) + erlotinib (E) versus placebo (P) + erlotinib (E) using VeriStrat in patients with previously treated nonsquamous NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 560. doi:10.1158/1538-7445.AM2015-560

Durability and characteristics of objective tumor responses with the innate immune cell modulator Imprime PGG in combination with standard of care frontline treatment for patients (Pts) with metastatic non-squamous NSCLC.

3070 Background: Recently, we reported numeric improvements in objective tumor response (OTR) and overall survival (16.1 vs 11.6 months median; HR = 0.66) with Imprime PGG (PGG) in a randomized (2:...

Promising Targets and Current Clinical Trials in Metastatic Non-Squamous NSCLC.

Lung adenocarcinoma is the most common subtype of lung cancer today. With the discovery of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and effective targeted therapy, personalized medicine has become a reality for patients with lung adenocarcinoma. Here, we review potential additional targets and novel therapies of interest in lung adenocarcinoma including targets within the cell surface (receptor tyrosine kinases EGFR, human epidermal growth factor receptor 2, RET, ROS1, mesenchymal–epidermal transition, TRK), targets in intracellular signal transduction (ALK, RAS–RAF–MEK, PI3K–AKT–PTEN, WNT), nuclear targets such as poly-ADP ribose polymerase, heat shock protein 90, and histone deacetylase, and selected pathways in the tumor environment. With the evolving ability to identify specific molecular aberrations in patient tumors in routine practice, our ability to further personalize therapy in lung adenocarcinoma is rapidly expanding.

An Open-Label, Multicenter, Randomized Phase Ib/II Study of Eribulin Mesylate Administered in Combination With Pemetrexed Versus Pemetrexed Alone as Second-Line Therapy in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer

IntroductionNew treatment options are needed for second-line therapy in patients with NSCLC. Patients and MethodsThis was a phase Ib/II study in patients with nonsquamous NSCLC in whom 1 previous platinum-based chemotherapy regimen had failed. Fifteen patients were enrolled in a dose escalation of eribulin mesylate in combination with pemetrexed (E+P). In phase II (n = 80), E+P at the maximum tolerated dose was compared with P. ResultsIn phase Ib, the maximum tolerated dose of E+P was defined as eribulin 0.9 mg/m2 with pemetrexed (500 mg/m2) each on day 1 of a 21-day cycle. In phase II, adverse events were comparable between groups. PFS and OS were similar between treatment groups. Median PFS was 21.4 weeks for E+P (n = 26; 95% confidence interval [CI], 12.7-39.6) and 23.4 weeks for P (n = 29; 95% CI, 17.1-29.9), with a hazard ratio of 1.0 (95% CI, 0.6-1.7). ConclusionDuring phase Ib, E+P was tolerated only at a markedly lower dosing intensity relative to the eribulin monotherapy regimen approved for breast cancer and used in phase II studies of NSCLC. At the selected phase II dosing regimen, E+P was generally safe and well tolerated but provided no therapeutic advantage for the second-line treatment of locally advanced or metastatic nonsquamous NSCLC.

12 VEGF autocrine survival signalling is mediated via neuropilin 1 receptor in NSCLC cells

Methods: Data on all tested patients was prospectively collected from the inauguration of the EGFR genetic service. There were three specific aims in the study. First, did the outcomes in an off-trial population with an often poor socio-economic status match those reported in a clinical trial population? Second, did the Scottish prevalence of common EGFR mutations reflect what has been described internationally? Finally, were there any interesting EGFR genetic variants and what was their potential response to erlotinib? Results: Between July 2012 and June 2013, 49 EGFR mutations were detected from 488 patients tested (10.04%) who had a new diagnosis of first line metastatic non-squamous NSCLC. Of those mutated cancers, 34 had a tyrosine kinase inhibitor (TKI) sensitising variant, 4 patients had a TKI resistance variant, 4 had both a TKI sensitising and resistance mutation, and 7 had mutations of uncharacterised clinical significance. One patient with a c.2543C>T; p.Pro848Leu mutation demonstrated a clinical response after two months of erlotinib treatment, a genetic variant with no prior description of benefit from EGFR inhibition. Conclusions: Interesting genetic EGFR variants have been identified in the west of Scotland NSCLC population, one of which has demonstrated a previously uncharacterised clinical response to erlotinib. To date, prevalence of EGFR mutation and response to TKI treatment in the west of Scotland has reflected that reported in an international trial population.