Kenneth Emancipator

Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer

BACKGROUND We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. METHODS We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. RESULTS Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached. CONCLUSIONS Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).

PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project

Introduction: The Blueprint Programmed Death Ligand 1 (PD‐L1) Immunohistochemistry (IHC) Assay Comparison Project is an industrial‐academic collaborative partnership to provide information on the analytical and clinical comparability of four PD‐L1 IHC assays used in clinical trials. Methods: A total of 39 NSCLC tumors were stained with four PD‐L1 IHC assays (22C3, 28‐8, SP142, and SP263), as used in the clinical trials. Three experts in interpreting their respective assays independently evaluated the percentages of tumor and immune cells staining positive at any intensity. Clinical diagnostic performance was assessed through comparisons of patient classification above and below a selected expression cutoff and by agreement using various combinations of assays and cutoffs. Results: Analytical comparison demonstrated that the percentage of PD‐L1–stained tumor cells was comparable when the 22C3, 28‐8, and SP263 assays were used, whereas the SP142 assay exhibited fewer stained tumor cells overall. The variability of immune cell staining across the four assays appears to be higher than for tumor cell staining. Of the 38 cases, 19 (50.0%) were classified above and five (13%) were classified below the selected cutoffs of all assays. For 14 of the 38 cases (37%), a different PD‐L1 classification would be made depending on which assay/scoring system was used. Conclusions: The Blueprint PD‐L1 IHC Assay Comparison Project revealed that three of the four assays were closely aligned on tumor cell staining whereas the fourth showed consistently fewer tumor cells stained. All of the assays demonstrated immune cell staining, but with greater variability than with tumor cell staining. By comparing assays and cutoffs, the study indicated that despite similar analytical performance of PD‐L1 expression for three assays, interchanging assays and cutoffs would lead to “misclassification” of PD‐L1 status for some patients. More data are required to inform on the use of alternative staining assays upon which to read different specific therapy‐related PD‐L1 cutoffs.

Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial

BACKGROUND Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer. As part of the phase 1b KEYNOTE-012 study, we aimed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. METHODS This study was a multicentre, open-label, phase 1b trial done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan. We enrolled patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Patients received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred. Response was assessed every 8 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary objectives were safety in patients who received at least one dose of pembrolizumab and the proportion of patients achieving overall responses in patients who received at least one pembrolizumab dose and who either had a post-baseline scan or who discontinued therapy because of clinical disease progression or a treatment-related adverse event before the first post-baseline scan. The study is registered with ClinicalTrials.gov, number NCT01848834, and is ongoing but no longer enrolling patients. FINDINGS From Oct 23, 2013, to May 5, 2014, 39 patients were enrolled. 36 were evaluable for response by central assessment. Eight (22%, 95% CI 10-39) patients were judged to have had an overall response at central review; all responses were partial. All 39 patients were included in the safety analyses. Five (13%) patients had a total of six grade 3 or 4 treatment-related adverse events, consisting of two cases of grade 3 fatigue, one case each of grade 3 pemphigoid, grade 3 hypothyroidism, and grade 3 peripheral sensory neuropathy, and one case of grade 4 pneumonitis. No treatment-related deaths occurred. INTERPRETATION In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 trials. FUNDING Merck & Co.

Programmed Death-Ligand 1 Expression and Response to the Anti–Programmed Death 1 Antibody Pembrolizumab in Melanoma

Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort.

LBA6008 Background: Pembrolizumab (MK-3475) is a humanized monoclonal antibody that blocks interaction of PD-1 with its ligands, PD-L1 and PD-L2, thereby promoting activity of tumor-specific effector T cells. KEYNOTE 012 (NCT01848834) had previously demonstrated clinical activity of pembrolizumab 10 mg/kg every 2 weeks in patients (pts) with recurrent/metastatic SCCHN enriched for PD-L1-positive tumors with a response rate of 20%. We now report on the larger SCCHN expansion cohort of KEYNOTE 012, irrespective of biomarker status using a 3-weekly fixed dose. METHODS Pts with advanced SCCHN irrespective of PD-L1 expression or HPV status received a fixed dose of 200 mg pembrolizumab, intravenously, every 3 weeks. Pts were evaluated every 8 weeks with radiographic imaging. The primary end point was overall response rate (ORR) per investigator assessment (RECIST 1.1). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were assessed according to CTCAE v4. PD-L1 was assessed retrospectively by immunohistochemistry. RESULTS 132 pts with recurrent/metastatic SCCHN were enrolled. Mean (SD) age was 58.9 (9.7) years; 83.3% were male; 56.8% had ≥ 2 lines of therapy for recurrent disease. 73/132 pts (55.3%) remain on treatment. Out of 132 treated pts, 99 pts were available for this preliminary efficacy analysis with a post-baseline scan or discontinued therapy prior to the scan due to clinical progression or AE. ORR (confirmed and unconfirmed) per RECIST 1.1 was 18.2% (95% CI, 11.1-27.2) with 18 partial responses and 31.3% with stable disease. Biomarker analysis is ongoing and results will be presented. Drug-related AEs of any grade occurred in 47% of all enrolled pts, and drug-related grade ≥ 3 AEs occurred in 7.6%. The most common drug-related AEs ( ≥ 5%) of any grade were fatigue (12.1%), decreased appetite (6.8%), pyrexia (6.1%), and rash (5.3%). CONCLUSIONS Pembrolizumab given at a fixed dose of 200 mg every 3 weeks was well tolerated and demonstrated a clinically meaningful ORR of 18.2% in pts with recurrent/metastatic SCCHN. CLINICAL TRIAL INFORMATION NCT01848834.

Abstract CT105: MK-3475 (anti-PD-1 monoclonal antibody) for non-small cell lung cancer (NSCLC): Antitumor activity and association with tumor PD-L1 expression

Background: MK-3475, a humanized monoclonal IgG4 antibody against PD-1, has demonstrated durable antitumor activity in NSCLC and melanoma. Preliminary data presented at the 2013 World Congress of Lung Cancer showed a relationship between tumor PD-L1 expression and overall response to MK-3475. Here, we present updated data on tumor PD-L1 expression and its relationship with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Methods: In a phase I study, 38 previously treated NSCLC patients received MK-3475 10 mg/kg Q3W. Tumor response was assessed every 9 weeks by immune-related response criteria (irRC) per investigator review and by RECIST v1.1 per independent radiologic review. A new tumor biopsy performed within 60 days prior to the first dose of MK-3475 was required. Tumor PD-L1 expression was assessed by IHC. A potential cut point for PD-L1 expression was determined by the Youden Index from a receiver operating characterstics curve developed from the investigators’ irRC assessments. Results: Confirmed ORR for the entire cohort of 38 patients per investigators’ irRC assessments was 24%, median PFS was 9 weeks, and median OS was 51 weeks. PD-L1 IHC score was above a potential cut point in 9 patients and below a potential cut point in 22 patients; tumor was not submitted for or staining was not evaluable in 7 patients. Significant associations between tumor PD-L1 expression and ORR, PFS, and OS were observed (Table). Conclusions: Tumor PD-L1 expression levels were associated with tumor response, PFS, and OS in patients with NSCLC treated with MK-3475. The preliminary finding of minimal anti-tumor activity in patients whose tumors express low levels of PD-L1 suggests that PD-L1 is an important biomarker for patients with NSCLC treated with MK-3475. Citation Format: Leena Gandhi, Ani Balmanoukian, Rina Hui, Omid Hamid, Naiyer A. Rizvi, Natasha Leighl, Matthew Gubens, Jonathan W. Goldman, Gregory M. Lubiniecki, Kenneth Emancipator, Marisa Dolled-Filhart, Jared K. Lunceford, Michelle Niewood, Kevin Gergich, Edward B. Garon. MK-3475 (anti-PD-1 monoclonal antibody) for non-small cell lung cancer (NSCLC): Antitumor activity and association with tumor PD-L1 expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT105. doi:10.1158/1538-7445.AM2014-CT105

Prognostic Significance of PD-L1 in Patients with Non–Small Cell Lung Cancer: A Large Cohort Study of Surgically Resected Cases

Introduction: The aim of our analysis was to evaluate the prognostic effect of programmed cell death ligand‐1 (PD‐L1) expression in patients with non–small cell lung cancer (NSCLC). Methods: PD‐L1 expression among 1070 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis. Data were analyzed using Cox proportional hazard models adjusting for age, sex, smoking status, histologic type, stage, and performance status. Results: Sixty‐eight patients (6%) were strongly PD‐L1 positive and 410 (38%) were weakly PD‐L1 positive. A significantly higher prevalence of PD‐L1 positivity was observed among patients with squamous cell carcinoma and among stage IIIB and IV patients. PD‐L1 expression may be associated with poorer overall survival, with an adjusted hazard ratio of 1.56 (95% confidence interval [CI]: 1.08–2.26, p = 0.02) for strong PD‐L1 positivity, 1.18 (95% CI: 0.96–1.46; p = 0.12) for weak PD‐L1 positivity, and 1.23 (95% CI: 1.00–1.51; p = 0.05) for the combined strongly and weakly positive groups compared with PD‐L1 negativity. Negative prognostic effect of PD‐L1 expression was not statistically significant after adjustment for postoperative chemotherapy or radiotherapy. Similar results were observed for progression‐free survival. Among stage I patients, the disease recurrence rate was higher in the PD‐L1–positive versus in the PD‐L1–negative group (48% versus 27%, p < 0.001), with an adjusted hazard ratio for disease‐free survival of 2.01 (95% CI, 1.08–3.73; p = 0.03) for strong PD‐L1 positivity and 1.57 (95% CI, 1.17–2.11; p = 0.003) for weak PD‐L1 positivity compared with PD‐L1 negativity. Conclusions: Tumor PD‐L1 expression may be associated with poor prognosis in patients with NSCLC, although its significance weakens when postoperative therapy is considered.

Development of a Companion Diagnostic PD-L1 Immunohistochemistry Assay for Pembrolizumab Therapy in Non–Small-cell Lung Cancer

A companion diagnostic assay was codeveloped by Dako for pembrolizumab non–small-cell lung cancer clinical trials to detect PD-L1 expression by immunohistochemistry (IHC). This automated IHC assay has been analytically verified and validated using Dako’s autostainer Link 48 and 22C3 mouse anti-PD-L1 monoclonal antibody to detect the PD-L1 expression in formalin-fixed paraffin-embedded human tumor tissue specimens. The PD-L1 22C3 IHC assay was optimized for high sensitivity and specificity. Repeatability and reproducibility studies were conducted at Dako and at 3 Clinical Laboratory Improvement Amendments certified laboratories during assay development. The studies included: intersite and intrasite, interobserver and intraobserver, interinstrument, interoperator, interday, and interlot, and intraday and intrarun. All precision studies performed at Dako and external laboratories achieved >85% point-estimate agreements for all 3 agreement types (negative, positive, and overall). A clinical cutoff (tumor proportion score ≥50%) of PD-L1 expression was determined and evaluated through a phase 1 clinical trial (KEYNOTE-001) for advanced non–small-cell lung cancer patients treated with pembrolizumab. The treatment effect of pembrolizumab in the 61 subjects who had a tumor PD-L1 of tumor proportion score ≥50% was substantial, with an overall response rate of 41% (95% confidence interval, 28.6-54.3) as compared with 20.6% (95% confidence interval, 15.5-26.5) observed in the 223 subjects irrespective of PD-L1 status. PD-L1 IHC 22C3 pharmDx is a sensitive, precise, and robust companion diagnostic assay, which will facilitate safe and effective use for pembrolizumab in cancer patients.

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial

Background Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. Patients and methods In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Results Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%–49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18–37) and median overall survival was 22.1 months (95% CI 17.1–27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%–71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%–36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Conclusions Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%. Clinical trial name and number KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).

PD-L1 Expression and Survival among Patients with Advanced Non–Small Cell Lung Cancer Treated with Chemotherapy

BACKGROUND: Recent clinical trial results have suggested that programmed cell death ligand 1 (PD-L1) expression measured by immunohistochemistry may predict response to anti–programmed cell death 1 (PD-1) therapy. Results on the association between PD-L1 expression and survival among patients with advanced non–small cell lung cancer (NSCLC) treated with chemotherapy are inconsistent. MATERIAL AND METHODS: We evaluated the relationship between PD-L1 expression and overall survival (OS) among 204 patients with advanced NSCLC treated at Aarhus University Hospital, Aarhus, Denmark, from 2007 to 2012. PD-L1 expression was measured using a prototype immunohistochemistry assay with the anti–PD-L1 22C3 antibody (Merck). PD-L1 strong positivity and weak positivity were defined to be traceable to the clinical trial version of the assay. RESULTS: Twenty-five percent of patients had PD-L1 strong-positive tumors, and 50% had PD-L1 weak-positive tumors. No statistically significant association was found between PD-L1 expression and survival; adjusted hazard ratio of 1.34 (95% confidence interval, 0.88-2.03; median OS, 9.0 months) for the PD-L1 strong-positive group and 1.07 (0.74-1.55; median OS, 9.8 months) for the PD-L1 weak-positive group compared with the PD-L1–negative group (median OS, 7.5 months). No association was seen between PD-L1 expression and OS when PD-L1 expression levels were stratified by median or tertiles. CONCLUSIONS: In concordance with previous studies, we found PD-L1 measured by immunohistochemistry to be frequently expressed in patients with advanced NSCLC. However, PD-L1 expression is not a strong prognostic marker in patients with advanced NSCLC treated with chemotherapy.