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Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic SCLC: Results From the KEYNOTE-028 and KEYNOTE-158 Studies

Open ArchivePublished:December 20, 2019DOI:https://doi.org/10.1016/j.jtho.2019.12.109

      Abstract

      Introduction

      Pembrolizumab has shown clinical benefit in patients with previously treated recurrent or metastatic SCLC in the phase 1b multicohort study KEYNOTE-028 (NCT02054806) and the phase 2 multicohort study KEYNOTE-158 (NCT02628067). We present a pooled analysis of patients from KEYNOTE-028 and KEYNOTE-158 who had received two or more lines of previous therapy for SCLC.

      Methods

      Eligible patients were aged 18 years and above, had histologically or cytologically confirmed incurable recurrent or metastatic SCLC, had an Eastern Cooperative Oncology Group performance status of 1 and below, and had received two or more lines of previous therapy. Patients in KEYNOTE-028 were required to have a programmed death ligand 1 (PD-L1)–positive tumor. Patients received pembrolizumab (10 mg/kg every 2 weeks in KEYNOTE-028 or 200 mg every 3 weeks in KEYNOTE-158) for up to 2 years. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1, which is presented here per independent review.

      Results

      Eighty-three patients who had received two or more lines of previous therapy (KEYNOTE-028, n = 19; KEYNOTE-158, n = 64) were included. Median follow-up duration was 7.7 (range, 0.5–48.7) months. Objective response rate was 19.3% (95% confidence interval: 11.4–29.4); two patients had complete response (one with a PD-L1–positive tumor), and 14 patients had partial response (13 with PD-L1–positive tumors). The median duration of response was not reached (range, 4.1‒35.8+ mo; plus sign indicates ongoing response); 61% of responders had responses lasting 18 months or longer. Fifty-one patients (61.4%) experienced any-grade treatment-related adverse events; eight patients (9.6%) had grade 3 or higher events.

      Conclusions

      Pembrolizumab exhibited durable antitumor activity in a subset of patients with recurrent or metastatic SCLC who had undergone two or more previous lines of therapy, regardless of PD-L1 expression. Pembrolizumab was well tolerated.

      Keywords

      Introduction

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      Patients who require third-line or subsequent therapy for advanced SCLC have limited treatment options, all of which are associated with poor outcomes. Consequently, we analyzed data pooled from the SCLC cohorts from KEYNOTE-028 and KEYNOTE-158 studies involving patients who had received two or more lines of previous therapy to further explore the efficacy and safety of pembrolizumab monotherapy in this setting.

      Materials and Methods

      Eligibility Criteria

      The current pooled analysis includes patients from KEYNOTE-028 (phase 1b; ClinicalTrials.gov identifier, NCT02054806) and KEYNOTE-158 (phase 2; ClinicalTrials.gov identifier, NCT02628067) studies who had recurrent or metastatic SCLC and received pembrolizumab after two or more previous lines of therapy. KEYNOTE-028 and KEYNOTE-158 are open-label, multicohort studies that enrolled patients with 20 and more than 10 tumor types, respectively, including SCLC. In both the studies, patients were eligible if they were aged 18 years and above and had histologically or cytologically confirmed advanced (unresectable and/or metastatic) solid tumors that were incurable and ineligible for standard therapy. Eligible patients in both the studies had measurable disease per RECIST version 1.1 and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were excluded if they had previously received immune checkpoint inhibitor therapy, had central nervous system (CNS) metastases or carcinomatous meningitis (patients with CNS metastases could participate provided CNS metastases were previously treated and stable), had an active autoimmune disease within the past 2 years that required systemic treatment, or received immunosuppressive therapy within 7 days of the first dose of study drug. Provision of an archival or newly obtained tissue sample from a site that had not been previously irradiated for biomarker analysis was mandated in both the studies, but tumor PD-L1 positivity was required only for patients enrolled in KEYNOTE-028 (PD-L1 assessments are described below).
      These studies were conducted in compliance with local and national regulations and in accordance with the ethical principles listed in the Declaration of Helsinki. All patients provided informed consent for participation in the studies.

      Study Treatment

      Patients received pembrolizumab (10 mg/kg every 2 weeks in KEYNOTE-028 or 200 mg every 3 weeks in KEYNOTE-158) for up to 2 years or until documented disease progression, unacceptable toxicity, intercurrent illness preventing further study treatment, or withdrawal from study. Patients who achieved a complete response (CR) could discontinue pembrolizumab if they had received at least 24 weeks of pembrolizumab therapy (12 or more administrations for KEYNOTE-028 or eight or more administrations for KEYNOTE-158). Patients who had confirmed disease progression but were benefiting clinically at the time of confirmatory tumor imaging could continue pembrolizumab therapy. Patients in both KEYNOTE-028 and KEYNOTE-158 who experienced radiographic progression (per investigator per RECIST version 1.1) after initial treatment with pembrolizumab were eligible for up to 1 year of pembrolizumab retreatment if they met certain criteria. Patients in KEYNOTE-028 could receive retreatment if they stopped treatment after attaining a CR, had received at least 24 weeks of pembrolizumab therapy and received at least two pembrolizumab administrations after the initial CR, or had stable disease or better and discontinued after at least 24 months of therapy for reasons other than disease progression or intolerability. Patients in KEYNOTE-158 were eligible for retreatment if they stopped treatment after attaining a CR and had received 24 weeks of pembrolizumab therapy or received at least eight pembrolizumab administrations with at least two pembrolizumab administrations after the initial CR or if they had stable disease or better and discontinued after at least 24 months of therapy.

      Outcomes

      The primary end point for both the studies was ORR, defined as the proportion of patients with a CR or partial response (PR) per RECIST version 1.1. Secondary end points included duration of response (defined as the time from first documented CR or PR until first documented disease progression or death due to any cause per RECIST version 1.1), progression-free survival (PFS; defined as the time from treatment allocation to first documented disease progression per RECIST version 1.1), OS (defined as the time from treatment allocation to death due to any cause), and safety and tolerability.

      Assessments

      Tumor imaging by computed tomography or magnetic resonance imaging was performed at baseline (28 d before the first dose of study drug), with response assessments every 8 weeks for the first 6 months (KEYNOTE-028) or every 9 weeks for the first year (KEYNOTE-158) and every 12 weeks thereafter. The primary assessment of tumor response was by an independent central review per RECIST version 1.1 in KEYNOTE-158 and by the investigator per RECIST version 1.1 in KEYNOTE-028 (although the study protocol allowed for independent central assessment of response). For the current analysis, we evaluated response by independent central review. Adverse events (AEs) were monitored at every visit and for 30 days after the end of study treatment (90 d for serious AEs). AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. After documented disease progression or if a patient started a new anticancer therapy, survival status was monitored by telephone every 12 weeks.
      In both the studies, tumor PD-L1 status was centrally evaluated. In KEYNOTE-028, tumor samples were assessed using a laboratory-developed prototype immunohistochemistry assay (QualTek Molecular Laboratories, Goleta, CA) with the 22C3 antibody clone (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ). Samples were considered PD-L1 positive if they exhibited membranous PD-L1 expression in at least 1% of tumor and associated inflammatory cells or positive staining in the stroma.
      • Dolled-Filhart M.
      • Locke D.
      • Murphy T.
      • et al.
      Development of a prototype immunohistochemistry assay to measure programmed death ligand-1 expression in tumor tissue.
      In KEYNOTE-158, PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA), and samples with a PD-L1 combined positive score of at least 1 were considered positive. The combined positive score was the ratio of PD-L1–positive cells (tumor cells, lymphocytes, and macrophages) to the total number of tumor cells multiplied by 100.

      Statistical Analysis

      In this exploratory pooled analysis, all patients with SCLC with two or more lines of previous therapy who received at least one dose of pembrolizumab were assessed for safety; efficacy was assessed in those who had received at least one dose of pembrolizumab and had measurable disease at baseline. ORR was assessed by blinded independent central review per RECIST version 1.1, with 95% CIs calculated according to the exact binomial method (Clopper and Pearson Method). The duration of response, PFS, and OS were estimated by the Kaplan-Meier method.

      Results

      Patients and Treatment Exposure

      Of the 131 patients included in the SCLC cohorts in both the studies, this pooled efficacy and safety analysis included 83 patients with recurrent or metastatic SCLC (19 from KEYNOTE-028 and 64 from KEYNOTE-158) who had previously received two or more lines of therapy for advanced disease. The median age was 62 (range, 24–84) years; 53 patients (63.9%) were men, 30 (36.1%) had previously received three or more lines of therapy, and 13 (15.7%) had stable brain metastases at baseline (Table 1). Forty-two of 83 patients (50.6%) were administered radiation therapy to the brain before enrollment.
      Table 1Patient Demographics and Baseline Clinical Characteristics
      Characteristic
      Data are presented as n (%) unless otherwise noted.
      Patients N = 83
      Age, median (range), y62.0 (24–84)
       ≥65 y33 (39.8)
      Sex
       Male53 (63.9)
       Female30 (36.1)
      ECOG performance status
       025 (30.1)
       157 (68.7)
       Missing1 (1.2)
      Brain metastases
       Present13 (15.7)
       Absent70 (84.3)
      Number of previous lines of therapy
       253 (63.9)
       317 (20.5)
       49 (10.8)
       ≥54 (4.8)
      Baseline PD-L1 expression
      All patients in KEYNOTE-028 had PD-L1‒positive tumors (PD-L1 expression ≥1%) assessed using a laboratory-developed prototype immunohistochemistry assay (QualTek Molecular Laboratories, Goleta, CA) with the 22C3 antibody clone. PD-L1 positivity was not a requirement for KEYNOTE-158 but was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA); samples were PD-L1 positive if they had a combined positive score of ≥1.
       Positive47 (56.6)
       Negative28 (33.7)
       Not evaluable8 (9.6)
      Previous radiation therapy66 (79.5)
      Tumor size at baseline, median (range),
      Sum of the longest diameter of target lesions per independent central review.
      mm
      102.4 (15.4–340.6)
      ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1.
      a Data are presented as n (%) unless otherwise noted.
      b All patients in KEYNOTE-028 had PD-L1‒positive tumors (PD-L1 expression ≥1%) assessed using a laboratory-developed prototype immunohistochemistry assay (QualTek Molecular Laboratories, Goleta, CA) with the 22C3 antibody clone. PD-L1 positivity was not a requirement for KEYNOTE-158 but was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA); samples were PD-L1 positive if they had a combined positive score of ≥1.
      c Sum of the longest diameter of target lesions per independent central review.
      Patients were enrolled between March 24, 2014, and May 6, 2015, in KEYNOTE-028 and between February 4, 2016, and September 28, 2016, in KEYNOTE-158. The data cutoff in this analysis was July 31, 2018, for KEYNOTE-028 (approximately 3 years from the date of enrollment of the last patient) and July 13, 2018, for KEYNOTE-158 (approximately 2 years from the date of enrollment of the last patient). At data cutoff, the median duration of follow-up, defined as the time from the first dose to the date of data cutoff or death, whichever occurred first, was 7.7 (range, 0.5–48.7) months for pooled patient population. At the time of data cutoff, eight patients had completed therapy and two continued to receive pembrolizumab. The remaining 73 patients had discontinued pembrolizumab. The most common reason for treatment discontinuation was disease progression (n = 57), followed by AE (n = 6), patient withdrawal (n = 4), physician decision (n = 3), use of excluded medication (n = 2), and loss to follow-up (n = 1). No patient received second-course pembrolizumab (i.e., retreatment).

      Efficacy

      For all patients included in this analysis, the ORR was 19.3% (95% CI: 11.4–29.4). Two patients (2.4%) had CRs and 14 patients (16.9%) had PRs according to the independent review per RECIST version 1.1 (Table 2). Of the 16 responders, two patients had brain metastasis at baseline. Moreover, 14 of 16 patients (88%) with a response had PD-L1–positive tumors (assessed using 22C3 antibody–based assays; see Materials and Methods), which included one patient with CR and 13 with PR. The second patient with CR had PD-L1–negative tumor, and the other patient with PR had a nonevaluable tumor sample. Among the 16 patients who had a response, median duration of follow-up was 25.9 (range, 16.1–40.1) months. The median time to response was 2.1 (range, 1.7–4.1) months, and the median response duration was NR (range, 4.1‒35.8+ mo; Fig. 1). The Kaplan-Meier estimates for response durations of at least 12 and at least 18 months were 67.7% and 60.9%, respectively (Table 2). At the time of analysis, nine patients (10.8%), including both the patients with CRs, had an ongoing response, and six experienced disease progression after PR (Fig. 2A). Reductions from baseline in the sum of target lesion diameters occurred in 33 of the 75 evaluable patients (44%), with 22 patients (29%) experiencing a reduction in tumor size of at least 30% (Fig. 2B).
      Table 2Best Overall Response per Response Evaluation Criteria in Solid Tumors Version 1.1 by Independent Review
      ParameterEvaluable Patients
      Efficacy analyses included patients who received at least one dose of pembrolizumab and who had confirmed responses.


      N = 83
      Objective response, n (%; 95% confidence interval)16 (19.3; 11.4–29.4)
      Best overall response, n (%)
       CR2 (2.4)
       PR14 (16.9)
       SD15 (18.1)
       Non-CR/non-PD
      Persistence of at least one target lesion.
      1 (1.2)
       PD45 (54.2)
       No assessment
      Includes patients without postbaseline assessment.
      6 (7.2)
      Time to response,
      Assessed in patients with a best objective response of confirmed CR or PR.
      median (range), mo
      2.1 (1.7–4.1)
      Duration of response,
      From the product-limit (Kaplan-Meier) method for censored data.
      median (range), mo
      NR (4.1–35.8+)
      “+” indicates no progressive disease at time of last assessment.
      Kaplan-Meier estimate of number of patients with extended duration of response,
      From the product-limit (Kaplan-Meier) method for censored data.
      n (%)
       ≥12 mo10 (67.7)
       ≥18 mo9 (60.9)
      CR, complete response; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease.
      a Efficacy analyses included patients who received at least one dose of pembrolizumab and who had confirmed responses.
      b Persistence of at least one target lesion.
      c Includes patients without postbaseline assessment.
      d Assessed in patients with a best objective response of confirmed CR or PR.
      e From the product-limit (Kaplan-Meier) method for censored data.
      f “+” indicates no progressive disease at time of last assessment.
      Figure thumbnail gr1
      Figure 1Duration of response by Response Evaluation Criteria in Solid Tumors version 1.1 by independent review. Analysis included patients who achieved a confirmed complete or partial response with pembrolizumab therapy after at least two lines of previous therapy. Patients with an ongoing response were defined as those who were alive without disease progression, had not initiated a new cancer treatment, were not lost to follow-up, and whose last disease assessment was within 5 months of the data cutoff date. NR, not reached.
      Figure thumbnail gr2
      Figure 2Time to response and time to progression in individual patients with (A) a confirmed objective response on the basis of Response Evaluation Criteria in Solid Tumors version 1.1 by central radiology assessment and (B) target lesion changes from baseline on the basis of Response Evaluation Criteria in Solid Tumors version 1.1 by independent review. Percentage changes >100% were capped at 100%. Median duration of follow-up (defined as time from the first dose to date of data cutoff or death, whichever occurred first) among patients with a response was 25.9 (range, 16.1–40.1) months. CR, complete response; PD, progressive disease; PR, partial response.
      At data cutoff, 72 of 83 patients (86.7%) had a PFS event (Fig. 3A). The median PFS was 2.0 months (95% CI: 1.9–3.4), and the estimated 12- and 24-month PFS rates were 16.9% and 13.1%, respectively. Sixty-seven patients (80.7%) had died; the median OS was 7.7 months (95% CI: 5.2–10.1), and the estimated 12- and 24-month OS rates were 34.3% and 20.7%, respectively (Fig. 3B).
      Figure thumbnail gr3
      Figure 3Kaplan-Meier analysis of (A) progression-free survival on the basis of Response Evaluation Criteria in Solid Tumors version 1.1 by independent review and (B) overall survival. Tick marks represent censored patients. All patients received at least one dose of pembrolizumab therapy after at least two lines of previous therapy. Vertical dotted lines indicate 6- and 12-month overall and progression-free survival rates. CI, confidence interval.

      Safety

      The incidence, severity, and most frequently occurring treatment-related AEs and immune-mediated AEs or infusion reactions were similar among patients who had at least one or at least two previous lines of therapy (n = 131; Table 3). Here, we describe safety for patients who received pembrolizumab after two or more previous lines of therapy (n = 83). Treatment-related AEs occurred in 51 of 83 patients (61.4%) (Table 3). The most common treatment-related AEs were fatigue (12.0%), pruritus (12.0%), rash (12.0%), hypothyroidism (10.8%), and arthralgia (9.6%). Six patients (7.2%) had a grade 3 treatment-related AE (colitis [n = 2] and acute kidney injury, asthenia, pneumonitis, and secondary adrenocortical insufficiency [n = 1 each]). The only treatment-related nervous system disorders to occur in more than one patient were headache (grade 1, n = 1; grade 2, n = 1) and dizziness (grade 1, n = 2). There were no treatment-related grade 4 AEs. There were two fatal treatment-related AEs. One patient had grade 5 intestinal ischemia on day 279 that was first diagnosed on day 277 as a grade 4 event. The patient had previously been diagnosed with serious treatment-related grade 3 colitis and grade 1 cytokine-release syndrome. A second patient had grade 5 pneumonia that first manifested on day 44 and resulted in death on day 45. The patient did not experience any other serious treatment-related AE. Five patients (6.0%) discontinued pembrolizumab owing to a treatment-related AE.
      Table 3Summary of Adverse Events in a Pooled Analysis of Patients With SCLC Enrolled in KEYNOTE-028 and KEYNOTE-158 Studies
      ParameterPatients With ≥1 Previous Line of Therapy

      N = 131
      Patients With ≥2 Previous Lines of Therapy

      N = 83
      Patients With ≥1 AE, n (%)AnyGrade 3–5
      No grade 4 treatment-related AEs occurred.
      AnyGrade 3–5
      No grade 4 treatment-related AEs occurred.
      Treatment-related AEs79 (60.3)13 (9.9)51 (61.4)8 (9.6)
       Led to discontinuation9 (6.9)6 (4.6)5 (6.0)3 (3.6)
       Led to death
      Treatment-related AEs leading to death were pneumonia and intestinal ischemia (n = 1 each), and encephalopathy in an additional patient who had at least one previous line of therapy.
      3 (2.3)3 (2.3)2 (2.4)2 (2.4)
       Occurring in ≥5% of patients
      Fatigue18 (13.7)1 (0.8)10 (12.0)0
      Pruritus14 (10.7)1 (0.8)10 (12.0)0
      Rash15 (11.5)010 (12.0)0
      Hypothyroidism13 (9.9)09 (10.8)0
      Arthralgia14 (10.7)1 (0.8)8 (9.6)0
      Asthenia12 (9.2)1 (0.8)7 (8.4)1 (1.2)
      Dry skin9 (6.9)07 (8.4)0
      Nausea13 (9.9)07 (8.4)0
      Decreased appetite11 (8.4)06 (7.2)0
      Diarrhea12 (9.2)1 (0.8)6 (7.2)0
      Hyperthyroidism7 (5.3)05 (6.0)0
      Myalgia11 (8.4)1 (0.8)5 (6.0)0
      Immune-mediated AEs and infusion reactions
      Events are based on a specified list provided by the sponsor and were considered regardless of attribution to treatment- or immune-relatedness by the investigator. No grade 4 or 5 immune-mediated AEs or infusion reactions occurred.
      27 (20.6)6 (4.6)20 (24.1)5 (6.0)
       Hypothyroidism13 (9.9)09 (10.8)0
       Hyperthyroidism7 (5.3)05 (6.0)0
       Infusion reactions3 (2.3)03 (3.6)0
       Colitis3 (2.3)2 (1.5)2 (2.4)2 (2.4)
       Severe skin reactions3 (2.3)1 (0.8)1 (1.2)0
       Adrenal insufficiency2 (1.5)1 (0.8)1 (1.2)1 (1.2)
       Pneumonitis2 (1.5)1 (0.8)1 (1.2)1 (1.2)
       Nephritis2 (1.5)01 (1.2)0
       Thyroiditis2 (1.5)02 (2.4)0
       Pancreatitis1 (0.8)1 (0.8)1 (1.2)1 (1.2)
       Hepatitis1 (0.8)01 (1.2)0
      AE, adverse event.
      a No grade 4 treatment-related AEs occurred.
      b Treatment-related AEs leading to death were pneumonia and intestinal ischemia (n = 1 each), and encephalopathy in an additional patient who had at least one previous line of therapy.
      c Events are based on a specified list provided by the sponsor and were considered regardless of attribution to treatment- or immune-relatedness by the investigator. No grade 4 or 5 immune-mediated AEs or infusion reactions occurred.
      Immune-mediated AEs and infusion reactions, regardless of attribution to study treatment as assessed by the investigator, occurred in 20 patients (24.1%) (Table 3). The most common of these were hypothyroidism (10.8%), hyperthyroidism (6.0%), and infusion reactions (3.6%). Five patients (6.0%) had grade 3 immune-mediated events; grade 3 events were colitis (2.4%) and adrenal insufficiency, pancreatitis, and pneumonitis (1.2% each). There were no grade 4 or 5 immune-mediated AEs or infusion reactions. Two patients (2.4%) discontinued treatment owing to an immune-mediated AE or infusion reaction. At the cutoff date, among those who experienced an immune-mediated AE or infusion reaction, six (30.4%) had received systemic corticosteroid treatment, and overall, the event(s) had fully resolved in 10 patients (50.0%) and were resolving in two patients (10.0%).

      Discussion

      Pembrolizumab exhibited antitumor activity in this exploratory pooled analysis of patients with recurrent or metastatic SCLC who had received two or more previous lines of therapy in KEYNOTE-028 and KEYNOTE-158. Tumor responses were durable, with most responders estimated to have a response duration lasting 18 or more months. The ORR was 19.3% for the pooled analysis compared with 18.7% for the overall population in KEYNOTE-158, in which patients were enrolled irrespective of their PD-L1 status, and 33.3% for KEYNOTE-028, which enrolled only patients with PD-L1–positive tumors. Median OS and PFS (7.7 and 2.0 mo, respectively) from this pooled analysis were similar to those observed in the overall populations (median OS was 9.7 and 8.7 mo and median PFS was 1.9 and 2.0 mo for KEYNOTE-028 and KEYNOTE-158, respectively).
      • Ott P.A.
      • Elez E.
      • Hiret S.
      • et al.
      Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study.
      ,
      • Chung H.C.
      • Lopez-Martin J.A.
      • Kao S.C.-H.
      • et al.
      Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158.
      The median OS of 7.7 months and median duration of response (NR) reported here for pembrolizumab are indicative of clinical benefit in the third-line or later setting. As a point of comparison, real-world studies have reported a median OS of 4.4 months and a median duration of response of 2.6 months for patients receiving third-line systemic therapy for SCLC.
      • Coutinho A.D.
      • Shah M.
      • Lunacsek O.E.
      • Eaddy M.
      • Willey J.P.
      Real-world treatment patterns and outcomes of patients with small cell lung cancer progressing after 2 lines of therapy.
      Nevertheless, our analysis lacks a comparator arm, and caution should be exercised with cross-study comparisons. Pembrolizumab was well tolerated among patients included in this analysis. Toxicities were consistent regarding both incidence and severity in the SCLC cohorts of KEYNOTE-028 and KEYNOTE-158 and in those of other studies evaluating pembrolizumab monotherapy.
      • Ott P.A.
      • Elez E.
      • Hiret S.
      • et al.
      Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study.
      ,
      • Chung H.C.
      • Lopez-Martin J.A.
      • Kao S.C.-H.
      • et al.
      Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158.
      ,
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      ,
      • Mok T.S.K.
      • Wu Y.-L.
      • Kudaba I.
      • et al.
      Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
      Immune-mediated AEs and infusion reactions (including episodes of adrenal insufficiency, colitis, hyperthyroidism, infusion reaction, nephritis, pancreatitis, pneumonitis, and thyroiditis) were managed using systemic corticosteroids. No unexpected toxicities were observed after treatment with pembrolizumab. Pembrolizumab monotherapy provides a treatment option that is better tolerated than chemotherapy in the heavily pretreated third-line setting.
      Other clinical studies have evaluated anti–PD-1 and anti–PD-L1 antibodies as therapies for previously treated SCLC. In the phase 1/2 CheckMate 032 study,
      • Antonia S.J.
      • Lopez-Martin J.A.
      • Bendell J.
      • et al.
      Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.
      in patients with recurrent or metastatic SCLC who had received two or more previous lines of therapy, the ORR with nivolumab (3 mg/kg) was 12%, and the median duration of response was 17.9 months (95% CI: 7.9–42.0).
      • Ready N.
      • Farago A.F.
      • de Braud F.
      • et al.
      Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032.
      ,
      • Hellmann M.
      • Antonia S.
      • Ponce S.
      • et al.
      Nivolumab alone or with ipilimumab in recurrent small cell lung cancer (SCLC): 2-year survival and updated analyses from the CheckMate 032 trial.
      However, the phase 3 CheckMate 331 study did not show significantly improved OS for nivolumab versus chemotherapy (topotecan or amrubicin) as a second-line therapy in patients with previously treated limited- or extensive-stage SCLC.
      • Reck M.
      • Vicente D.
      • Ciuleanu T.
      • et al.
      Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): results from CheckMate 331.
      In addition, the anti–PD-L1 inhibitors atezolizumab and durvalumab have been evaluated as monotherapies in patients with previously treated SCLC. Although early phase results have reported a potential of atezolizumab monotherapy for previously treated extensive-stage SCLC,
      • Sequist L.V.
      • Chiang A.
      • Gilbert J.M.
      • et al.
      Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC).
      second-line treatment with atezolizumab did not improve ORR, PFS, or OS compared with chemotherapy (topotecan or re-induction) among patients with relapsed SCLC in the phase 2 IFCT-1603 study.
      • Pujol J.L.
      • Greillier L.
      • Audigier-Valette C.
      • et al.
      A randomized non-comparative phase II study of anti-programmed cell death-ligand 1 atezolizumab or chemotherapy as second-line therapy in patients with small cell lung cancer: results from the IFCT-1603 Trial.
      The SCLC expansion cohort from a phase 1/2 study (ClinicalTrials.gov identifier, NCT01693562) reported that durvalumab monotherapy was associated with an ORR of 9.5% in patients (2/21) with pretreated extensive-stage SCLC; the two patients with PR had durable responses (14.6 and 29.5+ mo).
      • Goldman J.W.
      • Dowlati A.
      • Antonia S.J.
      • et al.
      Safety and antitumor activity of durvalumab monotherapy in patients with pretreated extensive disease small cell lung cancer (ED-SCLC).
      This retrospective pooled analysis combined data from two early phase multicohort studies with some variation in study design. Patients in KEYNOTE-028 and KEYNOTE-158 received different regimens of pembrolizumab (10 mg/kg every 2 wk and 200 mg every 3 wk, respectively); however, previous studies have shown that weight-based dosing and fixed dosing result in comparable drug exposure, with no major differences observed in safety and efficacy in patients with NSCLC.
      • Chatterjee M.
      • Turner D.C.
      • Felip E.
      • et al.
      Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.
      • Freshwater T.
      • Kondic A.
      • Ahamadi M.
      • et al.
      Evaluation of dosing strategy for pembrolizumab for oncology indications.
      • Abdel-Rahman O.
      Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review.
      Another difference in the design of the two studies was that patient eligibility required PD-L1–positive tumors for KEYNOTE-028, whereas the KEYNOTE-158 study enrolled patients irrespective of their PD-L1 status. Although there were differences in the assessment of PD-L1 expression between the two studies, both used the anti–PD-L1 antibody clone 22C3 to evaluate PD-L1 expression in the tumor and stroma. Finally, the slightly more frequent imaging schedule in KEYNOTE-028 versus KEYNOTE-158 might have resulted in marginally earlier assessments of response or progression. In both KEYNOTE-028 and KEYNOTE-158, response assessments per RECIST version 1.1 were prespecified and were employed in this analysis.
      Patients with SCLC now have a number of immunotherapy treatment options.
      National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology (NCCN guidelines). Small cell lung cancer. 1.2019 Version.
      Based on the results of KEYNOTE-028 and KEYNOTE-158 studies, pembrolizumab was recently approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic SCLC with disease progression during or after platinum-based chemotherapy and at least one other prior line of therapy.
      Merck Sharp & Dohme Corp
      KEYTRUDA® (pembrolizumab) full prescribing information.
      Similarly, nivolumab has been approved for the treatment of patients with SCLC after treatment with platinum and at least one other therapy.
      Bristol-Myers Squibb
      OPDIVO® (nivolumab) full prescribing information.
      For patients with extensive-stage disease, the phase 3 IMpower133 study reported that first-line treatment with the combination of atezolizumab plus carboplatin-etoposide improved OS and PFS compared with carboplatin-etoposide alone in the first-line setting,
      • Horn L.
      • Mansfield A.S.
      • Szczesna A.
      • et al.
      First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.
      and similarly, results from the CASPIAN study reported that first-line treatment with durvalumab plus platinum-etoposide improved OS and PFS.
      • Paz-Ares L.
      • Dvorkin M.
      • Chen Y.
      • et al.
      Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.
      To investigate further, KEYNOTE-604 (ClinicalTrials.gov identifier, NCT03066778), a phase 3 double-blind, placebo-controlled study of pembrolizumab in combination with etoposide and platinum chemotherapy as a first-line therapy in patients with extensive-stage SCLC is currently ongoing. In the context of these trials evaluating anti–PD-(L)1 therapy for patients with newly diagnosed extensive-stage disease,
      National Comprehensive Cancer Network
      NCCN clinical practice guidelines in oncology (NCCN guidelines). Small cell lung cancer. 1.2019 Version.
      it is important to note that patients with previous exposure to anti–PD-1 or anti–PD-L1 therapy were excluded from the KEYNOTE-028 and KEYNOTE-158 studies. In addition, it is important to note that there have been ongoing efforts to identify predictive biomarkers for pembrolizumab (and other anti–PD-1 or anti–PD-L1 agents) that might assist in patient selection. Results from an analysis of the KEYNOTE-158 study (including patients from the SCLC cohort) suggested higher response rates among patients with high tumor mutation burden than among those without high tumor mutation burden.
      • Marabelle A.
      • Fakih M.G.
      • Lopez J.
      • et al.
      Association of tumor mutational burden with outcomes in patients with select advanced solid tumors treated with pembrolizumab in KEYNOTE-158.
      Patients with SCLC for whom first- and second-line systemic therapies have failed have limited treatment options. In this pooled analysis of patients with recurrent or metastatic SCLC that progressed after two or more previous lines of therapy, pembrolizumab had promising antitumor activity with durable clinical benefit, and no new safety signals were identified. This pooled analysis supports the use of pembrolizumab monotherapy for patients with SCLC as a third-line or later therapy.

      Acknowledgments

      This project was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The sponsor participated in study design; data collection, analysis, and interpretation; report writing (including support for medical writing assistance); and in the decision to submit the article for publication. The authors thank the patients and their families and caregivers for participating in this study and all investigators and site personnel. Medical writing assistance was provided by Charlotte Majerczyk, PhD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

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