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L. Gandhi
Moderator of
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 11
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.01 - Prior TKI Therapy in NSCLC EGFR Mutant Patients Associates with Lack of Response to Anti-PD-1 Treatment (ID 2172)
16:45 - 16:50 | Author(s): E.B. Garon, B. Wolf, A. Lisberg, K.Y. Kim, J.M. Horton, N. Kamranpour, K. Chau, P. Abarca, M.L. Spiegel, M. Han, W. Sago, S. Hu-Lieskovan, K. Das, W.D. Wallace, D.J. Slamon, S.M. Dubinett, J.W. Goldman
- Abstract
- Presentation
Background:
Programmed cell death-1 (PD-1) inhibitors have shown significant potential to induce durable responses in non-small cell lung cancer (NSCLC). Although responses have been seen in patients (pts) whose tumors harbor epidermal growth factor receptor (EGFR) mutations (EGFRm), data to date with inhibitors of PD-1, or its ligand PD-L1, suggest that responses are less frequent in EGFRm NSCLC. Studies in which EGFRm pts receive EGFR tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors in sequence or concurrently are being conducted. However, based on the high response rate with EGFR TKIs in EGFRm pts, PD-1 inhibition does not precede the EGFR TKIs in these study designs.
Methods:
We evaluated data from our experience at UCLA as part of the KEYNOTE-001 clinical trial, in which pts received pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Early in the trial, an amendment excluded EGFRm, EGFR TKI naïve pts, however a subsequent amendment allowed such pts if their mutation was non-sensitizing to approved EGFR TKIs. Although the trial employed central radiographic assessment by RECIST v1.1 (available to the sponsor but not the sites), clinical decisions and the assessment we describe were based on investigator-assessed immune-related response criteria. Groups were compared using Fisher’s exact test. Western blot was performed using standard techniques, exposing human non-small cell lung cancer cell lines HCC-827, H1975, Calu3 and H460 to erlotinib or afatinib at 1µM or control using the antibody PD-L1 mAb #1368 (Cell Signaling) and α-tubulin antibody #2144 (Cell Signaling).
Results:
We enrolled 29 EGFRm pts. 2 of 3 EGFR TKI naïve pts experienced a partial response (PR) compared to 1 of 26 enrolled after a prior EGFR TKI (p<0.001). 18 of these 29 pts had a 9 week scan. Of these, PR was seen in both EGFR TKI naïve pts (one L858R mutation and one exon 20 insertion) compared to 1 of 16 enrolled after a prior EGFR TKI (p<0.001). Of note, a similar trend of increased responses in EGFR TKI naïve pts was not seen in EGFR wild type pts. In vitro experiments using erlotinib and afatinib showed unchanged PD-L1 levels in cell lines not inhibited by the EGFR TKI used, but reduced PD-L1 in EGFRm cell lines inhibited by the TKI. Of note, the only responder among the EGFR TKI-treated EGFRm pts was one of only 4 of the 16 scanned post-TKI pts who had a non-sensitizing mutation. So, 0 of 22 EGFRm pts with a sensitizing mutation responded after an EGFR TKI.
Conclusion:
A retrospective analysis in EGFRm NSCLC showed a strong correlation between response and lack of prior EGFR TKI treatment. PD-L1 levels decrease in response to an EGFR TKI in cell lines sensitive to the TKI. Immunohistochemistry evaluating the presence and location of relevant proteins and immune effector cells are ongoing as is whole exome sequencing. These results have implications for the design of clinical trials of PD-1 inhibitors in EGFRm pts. Supported by: 1K23CA149079, One Ball Matt Memorial Golf Tournament, Kasdan Family
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MINI03.02 - PD-L1 Displays a Funtional Effect in the Acquired Chemoresistance in Lung Cancer (ID 3187)
16:50 - 16:55 | Author(s): P. Zhang
- Abstract
- Presentation
Background:
Although neoadjuvant chemotherapy (NAC) for advanced lung cancer can improve operability and local disease control, the duration of benefit is limited before resistance develops. PD-L1, which was a co-stimulatory molecule,interacting with PD-1, has a crucial role in T-cell regulation in immune response. Interest remains in combining chemotherapy and immune therapies to overcome resistance.
Methods:
In the study, we used immunohistochemistry, real-time PCR and flow cytometry techniques to investigatethe correlation between overall survival (OS) and disease free survival (DFS) of lung cancer patients and the expression of programmed cell death ligand1 (PD-L1) and the effect of NAC on the expression of PD-L1 in lung cancer cells.
Results:
Firstly, we identified PD-L1 was uprelugated in the SD lung cancer patient by the RNA-seq analysis. Therefore, we performed IHC evaluation in the total 194 patients of NSCLC. The patients with PD-L1 (−) had much better OS compared to those who were PD-L1 (+), and a high PD-L1 expression level in the cancer cells was significantly correlated with a shorter OS and DFS in patients with NAC from the 194 patient (n=78). Meanwhile,in patients who had stable disease (SD) to NAC, there was a rise in the expression of PD-L1, and patients with NAC (n=78) had significantly high rate of positive PD-L1 expression compared with those without NAC (n=116, p= 0.001). The chemotherapy of lung cancer can induce the expression of PD-L1, which may be one of the resistance mechanisms of NAC. Changes in PD-L1 expression were examined in vitro and vivo. Inhibition of the PI3K/AKT pathway reduced the up-regulation of PD-L1 induced by cisplatin, suggesting an involvement of PI3K/AKT pathway in up-regulation of PD-L1.Moreover, knock down of PD-L1 can lead to an increase in apoptosis, as well as cisplatin-induced apoptosis. And caspase7 might play an important role in the apoptosis of lung cancer cells after the knockdown of PD-L1.
Conclusion:
These findings support provide a relationship between PD-L1 expression and chemoresistance. All in all, these results suggest the use of PD-L1 inhibitor with chemotherapy after surgery, in lung cancer patients who received NAC.
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MINI03.03 - Pembrolizumab 2 mg/kg Q3W for Previously Treated, PD-L1-Positive Advanced NSCLC (ID 3024)
16:55 - 17:00 | Author(s): O. Flotten, E.B. Garon, H. Arkenau, R. Hui, L. Gandhi, E. Felip, H. Lena, F. Cappuzzo, L. Horn, M. Gubens, J. Zhang, G. Lubiniecki, E. Im, M. Hellmann
- Abstract
- Presentation
Background:
In patients with previously treated NSCLC enrolled in KEYNOTE-001 (NCT01295827), the anti–PD-1 antibody pembrolizumab (MK-3475) has demonstrated promising efficacy and manageable safety when given at dosages of 10 mg/kg once every 2 weeks (Q2W) or once every 3 weeks (Q3W). In a prospectively defined validation set from KEYNOTE-001, the greatest efficacy was observed in patients whose tumors expressed PD-L1 in ≥50% of tumor cells. Here, we present data for patients with previously treated, PD-L1–positive advanced NSCLC enrolled in a KEYNOTE-001 expansion cohort added to evaluate pembrolizumab 2 mg/kg Q3W.
Methods:
Patients had measurable disease, ECOG performance status of 0 or 1, and adequate organ function. Prior therapy with ≥1 platinum-doublet chemotherapy regimen was required; an appropriate tyrosine kinase inhibitor was required for patients with sensitizing EGFR mutations or ALK translocations. All patients had PD-L1–positive tumors, defined as staining in ≥1% of tumor cells as determined by a prototype IHC assay using the 22C3 antibody. The percentage of PD-L1–stained tumor cells was also determined by a clinical trial IHC assay using the same antibody. Patients received pembrolizumab 2 mg/kg Q3W until investigator-determined progression according to immune-related response criteria, intolerable toxicity, patient withdrawal, or investigator decision. Response was assessed centrally every 9 weeks by RECIST v1.1.
Results:
Of the 55 patients enrolled, 41 (74.5%) received ≥2 prior therapies. Three (5.5%) patients experienced grade 3-5 drug-related AEs (grade 3 colitis and pneumonitis and grade 5 cardiorespiratory arrest). After a minimum of 27 weeks of follow-up by central radiology review of tumor imaging (median, 7.7 months; range, 6.4-9.7 months), confirmed overall response rate (ORR) in the 52 patients with centrally evaluable disease at baseline was 15.4% (95% CI, 6.9%-28.1%) and the disease control rate (DCR, complete response + partial response + stable disease) was 50.0% (95% CI, 35.8%-64.2%). At the time of analysis, all responses were ongoing, and the median response duration was not reached (range, 2.1+ to 6.2+ months). Median progression-free survival (PFS) was 3.3 months (95% CI, 2.0-6.0 months), with a 6-month PFS rate of 37.7%. Median overall survival (OS) was not reached, and the 6-month OS rate was 75.8%. In the 25 (45.5%) patients who had PD-L1 expression in ≥50% of tumor cells, confirmed ORR was 30.4% (95% CI, 13.2%-52.9%), DCR was 56.5% (34.5%-76.8%), median PFS was 4.2 months (95% CI, 1.9 months-NR), and 6-month PFS and OS rates were 49.0% and 81.8%, respectively.
Conclusion:
In this previously treated cohort of patients with PD-L1–positive advanced NSCLC, pembrolizumab 2 mg/kg Q3W demonstrated robust and durable antitumor activity, with improved efficacy in patients with PD-L1 staining in ≥50% of tumor cells.
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MINI03.04 - Discussant for MINI03.01, MINI03.02, MINI03.03 (ID 3305)
17:00 - 17:10 | Author(s): J.R. Brahmer
- Abstract
- Presentation
Abstract not provided
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MINI03.05 - Efficacy of Pembrolizumab in Key Subgroups of Patients with Advanced NSCLC (ID 3057)
17:10 - 17:15 | Author(s): M.D. Hellmann, E.B. Garon, L. Gandhi, R. Hui, J. Zhang, R. Rangwala, G. Lubiniecki, N.A. Rizvi
- Abstract
- Presentation
Background:
The humanized anti–PD-1 monoclonal antibody pembrolizumab (MK-3475) has demonstrated robust antitumor activity and a manageable safety profile in patients with advanced cancers, including NSCLC. In the first 495 patients with advanced NSCLC enrolled in multiple expansion cohorts of the phase 1b KEYNOTE-001 study (ClinicalTrials.gov, NCT01295827), pembrolizumab provided an overall response rate (ORR) of 19.4%. In a prospectively defined validation set, a relationship between tumor PD-L1 expression and pembrolizumab efficacy was demonstrated, such that patients with PD-L1 expression in ≥50% of cells had a 45.2% ORR compared with 16.5% and 10.7% in patients with PD-L1 expression in 1%-49% and <1% of cells, respectively. Using the total population of 550 patients with NSCLC treated with pembrolizumab in KEYNOTE-001, we assessed the relationship between antitumor activity and the level of PD-L1 expression in key patient subgroups.
Methods:
Patients with advanced NSCLC enrolled in the NSCLC-specific expansion cohorts of KEYNOTE-001 received pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or 10 mg/kg every 2 weeks (Q2W) until confirmed progression, intolerable toxicity, or investigator decision. Tumor PD-L1 expression was assessed by immunohistochemistry using a clinical-trial assay and scored as the proportion score (PS) (ie, percentage of tumor cells with membranous PD-L1 expression). Response was assessed every 9 weeks per RECIST v1.1 by central review. Patients evaluable for PD-L1 were those whose slides were prepared within 6 months of staining and for which a proportion score could be assigned.
Results:
ORR in the 550 patients who received ≥1 pembrolizumab dose was 18.9%. ORR was generally similar across subgroups (Table), although there may be a difference between ever and never smokers. Among the 409 patients evaluable for PD-L1 expression, ORR was highest in those with PS ≥50% as compared with PS 1%-49% or <1% (36.8%, 11.9%, and 10.0%, respectively). Within all subgroups, ORR was highest in patients with PS ≥50% (Table). Figure 1
Conclusion:
Pembrolizumab provides antitumor activity in a broad selection of subgroups of patients with advanced NSCLC. Improved response in patients whose tumors express PD-L1 in ≥50% of cells was observed for all subgroups. Ongoing analyses are investigating the interdependency between PD-L1 status, mutational status, and smoking.
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MINI03.06 - Phase II Studies of Nivolumab in Patients with Advanced Squamous (SQ) or Non-Squamous (NSQ) Non-Small-Cell Lung Cancer (NSCLC) (ID 1329)
17:15 - 17:20 | Author(s): K. Nakagawa, M. Nishio, T. Hida, H. Sakai, N. Nogami, S. Atagi, T. Takahashi, H. Nokihara, H. Saka, M. Takenoyama, S. Fujita, H. Tanaka, K. Takeda, M. Satouchi, H. Isobe, M. Maemondo, K. Goto, T. Hirashima, K. Minato, T. Tamura
- Abstract
- Presentation
Background:
Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a fully human IgG4, PD-1 immune-checkpoint inhibitor antibody, has shown durable clinical activity in previous[MS誠1] phase I and II trials in several tumor types. In March 2015, U.S. Food and Drug Administration (FDA) has approved Nivolumab for the treatment of patients with metastatic squamous (SQ) non-small-cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Here, we report the results of two phase II studies to evaluate the efficacy and safety of nivolumab in previously treated advanced SQ (JapicCTI-No.132072) and NSQ (JapicCTI-No.132073) NSCLC pts.
Methods:
Both studies required pts aged ≥ 20 years with an ECOG performance status of 0 or 1, stage IIIB/IV, or recurrent NSCLC and at least one prior chemotherapy including platinum containing regimen. Pts received nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity. The primary endpoint in both studies was the objective response rate (ORR) (RECIST v1.1). Planned sample size was 30 pts for SQ and 67 pts for NSQ, respectively (P~0~[MS誠1] =0.09 &[MS誠2] P~1~=0.26, P~0~=0.09 & P~1~=0.20 ; α=0.025 (one-side), 1-β=0.8).
Results:
From April 2013 to April 2014, a total of 111 NSCLC pts were enrolled in both studies (35 pts with SQ, 76 pts with NSQ, male/female: 81/30; PS 0/1: 46/55; aged 31 to 84 [median: 65.0] years; Stage IIIB/Stage IV/recurrence: 6/86/19). Objective response rates (ORRs) were 25.7% (9/35) [95% CI: 14.2, 42.1] in SQ and 19.7% (15/76) [95% CI: 12.3, 30.0] in NSQ, respectively. Complete Response was observed in 2.6% with NSQ. Median progression-free survival (mPFS) was 4.2 months (95% CI: 1.4, 7.1) for SQ and 2.8 months (95% CI: 1.4, 3.4) for NSQ, respectively. Median follow-up periods were 10.4 months and 8.4 months, respectively. Median duration of response was not reached in each study. Of 9 SQ pts and 15 NSQ pts who responded to nivolumab, durable and ongoing response was observed in 77.8% (7/9) and 80.0% (12/15), respectively. Median overall survival was not reached in either study. All Grade drug-related adverse events across both studies were 79.3% (88/111) and Grade 3-4 drug-related adverse events (G3-4 AEs) were observed in 16.2% (18/111) pts. Most common G3-4 AEs were lymphocyte count decreased 3.6% (4/111), hyponatremia 1.8% (2/111), interstitial lung disease 1.8% (2/111), pleural effusion 1.8% (2/111). Any grade of interstitial lung disease was observed in 4.5% (5/111) pts. No grade 5 AEs were observed.
Conclusion:
In these studies, nivolumab showed encouraging clinical efficacy in both SQ and NSQ NSCLC with a manageable safety profile.
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MINI03.07 - Clinical Attributes of Lung Cancer in US Community Oncology Practice: Implications for Immunotherapy (ID 733)
17:20 - 17:25 | Author(s): P. Reddy, D. Richards, B. Ulrich, V. Gunuganti, R. Jotte, S. Wilks, D. Waterhouse, M. Mohamed, J. Chandler, L. Schwartzberg, D. Khan, M. Hancock, C. Bromley, K. Kulig, M. Hussein
- Abstract
- Presentation
Background:
The majority of lung cancer in the US is treated in the community. A prospective cohort study of stage IV non-small cell lung cancer (NSCLC) and extensive disease small cell lung cancer (ED SCLC) is being conducted in 70 US community oncology practices (Figure) to assess current standards of care (SOC) and outcomes in anticipation of immunotherapy as a new treatment modality. This study establishes a historical comparator cohort in a “pre-immunotherapy era” of lung cancer treatment. Figure 1
Methods:
Patients with stage IV NSCLC and ED SCLC, at any point in their care, with documented dates of diagnosis and prior treatment, are eligible for inclusion. Patients are followed prospectively for 36 months or until death, with data abstraction from medical records into electronic case report forms. Patient-reported outcomes are prospectively collected, as are archival tumor tissue and serial blood samples from consenting patients for molecular profiling studies.
Results:
This early analysis focused on patient clinical attributes and tumor sample characteristics of relevance to non-clinical trial patient populations and to biomarker testing (Table). Of 1,183 cases enrolled to date, at enrollment 17.6% were ECOG performance status (PS) 2 or 3, 18.8% of patients had brain metastases, 22.2% were on systemic steroids, 6.7% had history of a specific autoimmune condition, and 49.5% had had tissue samples from core needle or surgical specimens.Figure 1
Conclusion:
Many immunotherapy clinical trials exclude patients with brain metastases, certain steroid use, poor PS, and autoimmune disease, yet a substantial proportion of community-based lung cancer patients present with these attributes. Approximately half of advanced stage patients have tissue specimens amenable to current SOC biomarker testing. Efforts to develop additional biomarker tests for lung cancer patients need to consider the reality of limited tissue sample availability in the community setting.
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MINI03.08 - Discussant for MINI03.05, MINI03.06, MINI03.07 (ID 3306)
17:25 - 17:35 | Author(s): J. Gray
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) exon 20 T790M mutation may have a predictive role before EGFR-tyrosine kinase inhibitors (TKIs) treatment and it also might have a prognostic role after acquired resistance to EGFR-TKIs. However, its role in EGFR-TKI rechallenge after failure of initial EGFR-TKIs in EGFR-mutant advanced non-small cell lung cancer (NSCLC) remains unknown.
Methods:
We retrospectively evaluated the clinical course of 515 EGFR-mutant advanced NSCLC patients who received first generation EGFR-TKIs (gefitinib or erlotinib) from December 2009 to November 2014 at Guangdong General Hospital. Of these 515 patients, 65 patients recieved same EGFR-TKI rechallenge, including 51 patients who underwent rebiopsy and secondary EGFR mutation detection after failure of initial EGFR-TKIs. EGFR detection was performed by Sanger sequencing or Amplification Refractory Mutation System (ARMS) methods. Progression-free survival (PFS) and overall survival (OS) were both calculated from commencement of EGFR-TKI rechallenge. Survival data were analyzed using the Kaplan-Meier method and log-rank test.
Results:
EGFR activating mutations still existed in all the 51 patients who received rebiopsy and 18 patients were with T790M mutation while 33 patients were without T790M. The median PFS for the T790M+ and T790M- groups were 1.8 months (95%CI 1.180~2.420) and 2.0 months (95%CI 1.100~2.900), respectively (P=0.261). The median OS for the two groups were 7.7 months (95%CI 6.548~8.852) and 6.8 months (95%CI 4.730~8.870), respectively (P=0.565). No statistical difference was found in PFS or OS between two groups(Figure 1). Figure 1 Fig 1. Kaplan-Meier curves of patients in two groups. (A)Progression-free survival. (B) Overall survival.
Conclusion:
EGFR T790M mutation is neither a predictive nor a prognostic factor for first generation EGFR-TKI rechallenge in EGFR-mutant advanced NSCLC patients, indicating that whether T790M occurs or not, same EGFR-TKI rechallenge could not be recommended as a good strategy to overcome the resistance to first generation EGFR-TKIs.
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MINI03.10 - Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X (ID 951)
17:40 - 17:45 | Author(s): H.A. Wakelee, L.V. Sequist, S. Gadgeel, J. Soria, J.W. Goldman, H. Yu, R. Camidge, B.J. Solomon, S. Matheny, D. Despain, V. Papadimitrakopoulou
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. New insights into mutEGFR NSCLC suggest clonal heterogeneity – activating EGFR mutations are truncal (present in all tumor clones) and T790M is a dominant branch mutation with variable clonal frequency between patients and over time. The extent of this clonal heterogeneity may relate to rociletinib efficacy. Here we present preliminary findings to evaluate this hypothesis from an ongoing Phase 1/2 clinical trial.
Methods:
TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with metastatic or unresectable locally advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). Screening included mandatory tumor biopsy and T790M testing. For Phase 1, patients could be T790M negative, positive or unknown. For Phase 2, T790M negative patients (by validated central testing) could have a contemporaneous local T790M+ result.
Results:
As of March 2015, 36 patients were enrolled in TIGER-X who were T790M central negative by cobas® or Qiagen therascreen® and evaluable for efficacy. Sensitivity analysis indicated that the 2 assay platforms were comparable for T790M detection. 69% (25/36) were T790M negative centrally but positive locally; 4/36 (11%) were negative by both central and local testing; and 7/36 (19%) were centrally negative with no local result. Median number of previous TKIs was 1 and median number of previous therapies was 2; 81% (29/36) were treated with a TKI as their most recent prior therapy. In central negative/local+ patients the ORR was 40% (10/25). In central negative/local negative patients the ORR was 25% (1/4). The most common treatment emergent adverse events in this subset (all grades) were fatigue, diarrhea, nausea and hyperglycemia.
Conclusion:
These preliminary findings suggest that patients who test negative for T790M using a sensitive tissue test may still benefit from treatment with rociletinib. In part, this clinical activity may be driven by T790M tumor heterogeneity, demonstrated by the discordant T790M results described. In addition, inhibition of IGF-1R/IR by the previously reported (Soria 2014) rociletinib metabolite M502 may also be driving some of the activity observed. This possible explanation is important, since the response rates reported herein are higher than described for other T790M inhibitors in T790M-negative patients. Furthermore, TKI re-treatment effect is unlikely to be a major driver of these results, since the majority of patients came on study directly after progression on another EGFR TKI. To further explore these findings, the open-label TIGER-2 (NCT02147990) and the randomized Phase 3 TIGER-3 (NCT02322281) studies include T790M negative patients.
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MINI03.11 - Discussant for MINI03.09, MINI03.10 (ID 3307)
17:45 - 17:55 | Author(s): C. Rolfo
- Abstract
- Presentation
Abstract not provided
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Author of
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-079 - Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone as First-Line Therapy for NSCLC (ID 2993)
09:30 - 09:30 | Author(s): L. Gandhi
- Abstract
Background:
Platinum doublet chemotherapy with or without bevacizumab is the standard first-line therapy for patients with advanced NSCLC without EGFR sensitizing mutations or ALK rearrangement. Pembrolizumab (MK-3475), a humanized monoclonal antibody against PD-1 designed to block the interaction of PD-1 with its ligands PD-L1 and PD-L2, has shown efficacy and a manageable toxicity profile in patients with NSCLC treated at doses ranging from 2 mg/kg every 3 weeks to 10 mg/kg every 2 weeks. In 45 patients with treatment-naive advanced NSCLC treated in KEYNOTE-001, single-agent pembrolizumab has demonstrated a response rate of 26%.
Methods:
KEYNOTE-021 (ClinicalTrials.gov, NCT02039674) is an international, open-label, multi-arm, phase 1/2 trial of pembrolizumab for advanced NSCLC. After establishing the safety and tolerability of pembrolizumab plus carboplatin and pemetrexed in phase 1, a randomized phase 2 cohort comparing the efficacy of pembrolizumab plus carboplatin and pemetrexed with that of carboplatin and pemetrexed has been initiated. Key eligibility criteria for this cohort are previously untreated stage IIIB/IV nonsquamous NSCLC, no sensitizing EGFR mutation or ALK rearrangement, and ECOG PS 0-1. Patients will be randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg Q3W plus carboplatin and pemetrexed at standard doses or carboplatin and pemetrexed alone. Randomization will be stratified by PD-L1 expression determined by immunohistochemistry at a central laboratory (positive [membranous expression in ≥1% of tumor cells] vs negative). Pembrolizumab will be given for 24 months or until progression, intolerable toxicity, or investigator decision. Pembrolizumab may be continued beyond radiographic progression in eligible patients. Carboplatin and pemetrexed will be given for 4 cycles followed by maintenance pemetrexed, alone or with pembrolizumab. Patients allocated to the chemotherapy-alone arm who experience progression may cross over to the pembrolizumab arm of the study. AEs will be monitored throughout treatment and for 30 days thereafter. Response will be assessed every 6 weeks for the first 18 weeks, then every 9 weeks in year 1 and every 12 weeks in year 2. Survival follow-up will occur every 3 months after discontinuation of study treatment. Primary end point is progression-free survival (RECIST v1.1, central review); secondary end points include overall survival, objective response rate, and correlation of PD-L1 expression with antitumor activity. This cohort is currently enrolling patients.
Results:
Not applicable.
Conclusion:
Not applicable.
