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Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti–programmed death-1 therapy

Open AccessPublished:November 28, 2022DOI:https://doi.org/10.1016/j.ejca.2022.10.019

      Highlights

      • Treatment of advanced BRAFV600-wild type melanoma after anti–programmed death-1 failure is challenging.
      • Cobimetinib (C) + atezolizumab (A) combination was studied in this population.
      • A + C showed limited activity in patients with relapsed refractory disease.
      • The objective response rate was 14.6% and disease control rate was 38.8%.
      • No new safety signals were identified.

      Abstract

      Objective

      To evaluate the efficacy and safety of cobimetinib plus atezolizumab in the treatment of patients with advanced BRAFV600 wild-type melanoma who had progressed on prior anti‒programmed death-1 (PD-1) therapy.

      Patients and methods

      This phase 1b, open-label, international multicentre study enrolled 3 cohorts. Herein, we report on patients in cohorts A and B who had progressed on prior anti‒PD-1 therapy. Patients in cohort A received cobimetinib 60 mg once daily for 21 days followed by a 7-day break and concurrent intravenous atezolizumab 840 mg every 2 weeks. Patients in cohort B received the same dosing regimen as cohort A except for cycle 1 in which patients received cobimetinib only for the first 14 days prior to initiation of atezolizumab on cycle 1 day 15. Coprimary end-points were objective response rate and disease control rate. Secondary end-points were duration of response, progression free survival and overall survival.

      Results

      Between 19th June 2017 and 12th December 2018, 103 patients were enrolled. Median follow-up was 6.9 months (interquartile range, 4.8–10.1 months); objective response rate was 14.6% and disease control rate was 38.8% (95% confidence interval, 29.39–48.94). The median duration of response, progression-free survival and overall survival was 12.7 months, 3.8 months and 14.7 months, respectively. The most common adverse events were diarrhoea (75/103; 72.8%), dermatitis acneiform (57/103; 55.3%) and nausea (52/103; 50.5%). Thirty-four patients (33.0%) died: 33 (91.7%) due to progressive disease and one (1%) due to treatment-related oesophagitis.

      Conclusions

      Combination therapy with cobimetinib and atezolizumab in patients with advanced BRAFV600 wild-type melanoma with disease progression on or after prior anti‒PD-1 therapy demonstrated limited activity.

      Clinical trial registration

      This study is registered with ClinicalTrials.gov; NCT03178851;

      Keywords

      1. Introduction

      Treatment for advanced BRAFV600 wild-type melanoma following the failure of anti‒programmed cell death 1 (PD-1) monoclonal antibodies is often limited to single-agent ipilimumab or clinical trials. Most immune checkpoint inhibitors (ICIs) in the second-line setting have limited effectiveness and can result in toxicities. With an estimated 22%–60% of patients with metastatic melanoma relapsing after ICIs [
      • Trujillo J.A.
      • Luke J.J.
      • Zha Y.
      • Segal J.P.
      • Ritterhouse L.L.
      • Spranger S.
      • et al.
      Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma.
      ], there remains a critical unmet need for additional effective treatments in these patients.
      Targeting the mitogen-activated protein kinase pathway is highly effective in BRAF-mutated melanoma, which accounts for approximately half of all melanomas [
      • Ascierto P.A.
      • Kirkwood J.M.
      • Grob J.J.
      • Simeone E.
      • Grimaldi A.M.
      • Maio M.
      • et al.
      The role of BRAF V600 mutation in melanoma.
      ]. About 15%–30% of melanomas harbour an activating NRAS mutation and 14% harbour NF1 mutations (>50% of which result in loss of function) [
      Cancer Genome Atlas Network
      Genomic classification of cutaneous melanoma.
      ]. Thus, even in melanomas that do not harbour constitutively active mutant BRAF, the activation of other components of the RAS/RAF/MEK pathway is common. Preclinical models have demonstrated antitumour response with MEK inhibition through its effects on T cells [
      • Boni A.
      • Cogdill A.P.
      • Dang P.
      • Udayakumar D.
      • Njauw C.N.
      • Sloss C.M.
      • et al.
      Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.
      ]. The phase 3 NEMO study demonstrated a modest increase in progression-free survival (PFS) with the MEK inhibitor binimetinib compared with dacarbazine in patients with NRAS mutation-positive melanoma [
      • Dummer R.
      • Schadendorf D.
      • Ascierto P.A.
      • Arance A.
      • Dutriaux C.
      • Di Giacomo A.M.
      • et al.
      Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.
      ]. In addition, combination therapy with MEK inhibition plus anti‒PD-1/programmed death ligand-1 (PD-L1) has shown synergistic tumour growth inhibition in preclinical models [
      • Ebert P.J.R.
      • Cheung J.
      • Yang Y.
      • McNamara E.
      • Hong R.
      • Moskalenko M.
      • et al.
      MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade.
      ].
      Cobimetinib, a highly selective MEK1/MEK2 inhibitor, is approved for use in combination with vemurafenib for advanced BRAFV600 mutation-positive melanoma [
      • Larkin J.
      • Ascierto P.A.
      • Dreno B.
      • Atkinson V.
      • Liszkay G.
      • Maio M.
      • et al.
      Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.
      ]. Atezolizumab, a humanised immunoglobulin G1 monoclonal antibody that targets PD-L1, enhances tumour-specific T-cell responses and has demonstrated an antitumour activity in multiple tumour types including metastatic melanoma [
      • Fehrenbacher L.
      • Spira A.
      • Ballinger M.
      • Kowanetz M.
      • Vansteenkiste J.
      • Mazieres J.
      • et al.
      Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.
      ,
      • Rosenberg J.E.
      • Hoffman-Censits J.
      • Powles T.
      • van der Heijden M.S.
      • Balar A.V.
      • Necchi A.
      • et al.
      Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.
      ,
      • Hamid O.
      • Molinero L.
      • Bolen C.R.
      • Sosman J.A.
      • Munoz-Couselo E.
      • Kluger H.M.
      • et al.
      Safety, clinical activity, and biological correlates of response in patients with metastatic melanoma: results from a phase I trial of atezolizumab.
      ]. In a phase 1b multicohort study of anti-PD-L1/PD-1–naive patients with solid tumours, cobimetinib plus atezolizumab showed an objective response rate (ORR) of 50% and median PFS of 15.7 months in 10 patients with BRAFV600 wild-type melanoma [
      • Hellmann M.D.
      • Kim T.W.
      • Lee C.B.
      • Goh B.C.
      • Miller W.H.
      • Oh D.Y.
      • et al.
      Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.
      ].
      Herein, we report the results of a phase 1b study that evaluated the efficacy and safety of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma who had progressed on or after prior anti‒PD-1 therapy.

      2. Methods

      2.1 Study design and participants

      This open-label, multicentre phase 1b study (NCT0317-8851) was conducted at 18 sites in Australia, Spain and the United States. The study enrolled patients with BRAFV600 wild-type advanced melanoma who had progressed on or after prior anti-PD-1 therapy (cohorts A and B) or were treatment naive (cohort C). Data from cohorts A and B are presented here; results for cohort C are published separately [
      • de Azevedo S.J.
      • de Melo A.C.
      • Roberts L.
      • Caro I.
      • Xue C.
      • Wainstein A.
      First-line atezolizumab monotherapy in patients with advanced BRAF(V600) wild-type melanoma.
      ].
      Key eligibility criteria for cohorts A and B were aged ≥18 years with histologically confirmed stage IV or unresectable stage IIIc BRAFV600 wild-type melanoma, with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and disease progression on or after anti-PD-1 treatment (monotherapy or in combination with other agents) for metastatic melanoma. Patients in cohort B must have progressed on or after anti-PD-1 treatment within 12 weeks before the study start and have had ≥2 accessible lesions amenable to a biopsy. Detailed eligibility criteria are available under Supplementary Materials Table A1.
      The study was approved by the institutional ethics review board for each study site (Supplementary Materials Table A2) and was conducted in line with International Conference on Harmonization E6 guidelines for Good Clinical Practice and the regulations of the country in which it was conducted. All patients provided written informed consent before participation in the study.

      2.2 Procedures and biopsies

      Patients in cohort A received atezolizumab 840 mg intravenously every 2 weeks and cobimetinib 60 mg once daily for 21 days followed by a 7-day break in a 28-day cycle. Patients in cohort B had a regimen identical to cohort A, except for cycle 1, during which patients received cobimetinib 60 mg once daily only for the first 14 days and atezolizumab 840 mg intravenously beginning on cycle 1 day 15 and continued thereafter every 2 weeks.
      Study treatment continued until disease progression (i.e. confirmed 4 weeks later for clinically stable patients with a favourable benefit-risk assessment), death, initiation of subsequent anticancer therapy or unacceptable toxicity, whichever occurred first. Measurable and non-measurable lesions were documented at screening, and response assessments were subsequently assessed at 8-week intervals per RECIST v1.1.
      All patients were required to provide archival tissue (<5 years old) or a fresh biopsy for study entry (Supplementary Appendix Figure A1). Via a separate optional consent, patients in cohort A were requested to provide biopsies at baseline (before cycle 1 day 1) and 4–6 weeks after the first atezolizumab dose. Patients in cohort B consented to provide mandatory biopsies at baseline, on-treatment (cycle 1 days 10–14) and post-treatment (radiographic progression) and a second optional on-treatment biopsy (cycle 2 from 4 to 6 weeks after the first atezolizumab dose). Additional details on biopsy collection are provided under Supplementary Materials.

      2.3 Outcomes

      The coprimary efficacy end-points were ORR (proportion of patients with a complete response [CR] or a partial response [PR] on 2 consecutive occasions ≥4 weeks apart, per RECIST v1.1) and disease control rate (DCR; proportion of patients with a CR, PR, or stable disease [SD] at 16 weeks). Secondary efficacy endpoints were duration of response (DoR; time of first occurrence of a documented overall response to disease progression or death from any cause, whichever occurred first), overall survival (OS; time from Cycle 1, Day 1 to death from any cause) and PFS (time from Cycle 1, Day 1 to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first). Safety was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.

      2.4 Biomarker analyses

      Biomarker analyses were performed to evaluate outcomes according to tumour PD-L1 expression, tumour mutational burden (TMB), driver mutations and interferon expression on RNA sequencing. PD-L1 expression on tumour-infiltrating immune cells (ICs) was evaluated using PD-L1 monoclonal antibody (SP142; Ventana Medical Systems, Oro Valley, AZ, USA). CD8+ T cells in the tumour were determined by immunohistochemistry. TMB and driver mutation status were evaluated by next generation sequencing using the FoundationOne platform (Foundation Medicine, Cambridge, MA, USA). Further details on the biomarker assays and analysis are outlined in the Supplementary Materials.

      2.5 Statistical analyses

      The efficacy and safety analyses populations included all patients who received ≥1 dose of both study drugs. Time-to-event analyses were summarised using Kaplan–Meier methodology. All other results were summarised using descriptive statistics. Comparisons of biomarker subgroups were performed using a chi-square, Fisher exact or Kruskal–Wallis test.

      3. Results

      3.1 Patients

      Between 19th June 2017 and 12th December 2018, 103 patients were enrolled (n = 92 in cohort A, n = 11 in cohort B). Of these, the biomarker evaluable populations included 94 patients for the immunohistochemistry analysis, 85 patients for the FoundationOne™ next generation sequencing analysis and ≤6 patients for RNA sequencing analysis at different timepoints (Supplementary Table A3). All patients met eligibility criteria with BRAFV600 wild-type tumours per local laboratory tests; however, subsequent central testing identified BRAFV600 mutations in seven patients (V600E in 4 patients, V600K in 2 patients and V600R in 1 patient) and BRAF gene fusion in one patient.
      At data cutoff (28th May 2019), 45 of 92 patients in cohort A (48.9%) and 2 of 11 patients in cohort B (18.2%) had discontinued the study. Median duration of follow-up was 7.1 months (interquartile range, 4.7–10.1 months) in cohort A and 5.6 months (4.8–13.3 months) in cohort B. The median age of patients was 62.0 years, with 65% males (Table 1). Patients had received 295 prior anti-cancer treatments. Overall, 81 patients had ≥1 documented best response to ≥1 prior immunotherapies. Best response to previous immunotherapy was CR (3/114; 2.6%), PR (11/114; 9.6%), SD (18/114; 15.8%), PD (75/114; 65.8%), not evaluable (NE; 2/114; 1.8%) or not available (5/114; 4.4%). There were 59 (72.8%) patients with a best response of PD to prior immunotherapies.
      Table 1Patient demographics and baseline characteristics.
      Cohort ACohort BAll patients
      N9211103
      Age, y, median (range)62.5 (34–90)62.0 (43–74)62.0 (34–90)
      Sex
       Male59 (64.1)8 (72.7)67 (65.0)
       Female33 (35.9)3 (27.3)36 (35.0)
      Geographic region
       Europe22 (23.9)2 (18.2)24 (23.3)
       North America20 (21.7)5 (45.5)25 (24.3)
       South Asia50 (54.3)4 (36.4)54 (52.4)
      ECOG performance status
       067 (72.8)9 (81.8)76 (73.8)
       125 (27.2)2 (18.2)27 (26.2)
      Distant metastasis
      Per American Joint Committee on Cancer Staging Manual, 7th edition.
       M05 (5.4)1 (9.1)6 (5.8)
       M1a9 (9.8)1 (9.1)10 (9.7)
       M1b18 (19.6)4 (36.4)22 (21.4)
       M1c59 (64.1)5 (45.5)64 (62.1)
       Mx1 (1.1)01 (1.0)
      Number of disease sites, median (range)3 (1–11)3 (2–7)3 (1–11)
      Liver metastasis
       Present25 (27.2)2 (18.2)27 (26.2)
       Absent67 (72.8)9 (81.8)76 (73.8)
      Lactate dehydrogenase level
       >ULN40 (44.9)6 (54.4)46 (46.0)
       ≤ULN49 (55.1)5 (45.5)54 (54.0)
      PD-L1 status
      PD-L1 expression was assessed by immunohistochemistry using an SP142 antihuman PD-L1 rabbit monoclonal antibody (Ventana Medical Systems, Tucson, AZ, USA).
       IC026 (32.1)5 (55.6)31 (34.4)
       IC1/2/355 (67.9)4 (44.4)59 (65.6)
      Prior adjuvant therapy
      All prior cancer therapies including radiotherapy. Tumour sections stained for PD-L1 were categorized into subgroups defined by threshold levels of staining for PD-L1 expressing tumour-infiltrating ICs of any intensity (IC0 <1%; IC1/2/3 ≥ 1%). Abbreviations: ECOG, Eastern Cooperative Oncology Group; IC, immune cell; PD-L1, programmed death-ligand 1; ULN, upper limit of normal.
       Yes37 (40.2)7 (63.6)44 (42.7)
       No55 (59.8)4 (36.4)59 (57.3)
      Prior adjuvant ipilimumab
       Yes12 (13.0)2 (18.2)14 (13.6)
       No80 (87.0)9 (81.8)89 (86.4)
      Prior treatment for brain metastases9 (9.8)1 (9.1)10 (9.7)
      Median time from initial melanoma diagnosis to study entry, mo (range)94.0 (15.2–942.7)81.2 (49.8–362.1)93.4 (15.2–942.7)
      Biomarker evaluable population, n
      BRAF mutant/fusion8
      NF1 mutant17
      RAS mutant42
       Triple wild type19
      Data represent N (%), unless otherwise specified.
      a Per American Joint Committee on Cancer Staging Manual, 7th edition.
      b PD-L1 expression was assessed by immunohistochemistry using an SP142 antihuman PD-L1 rabbit monoclonal antibody (Ventana Medical Systems, Tucson, AZ, USA).
      c All prior cancer therapies including radiotherapy. Tumour sections stained for PD-L1 were categorized into subgroups defined by threshold levels of staining for PD-L1 expressing tumour-infiltrating ICs of any intensity (IC0 <1%; IC1/2/3 ≥ 1%). Abbreviations: ECOG, Eastern Cooperative Oncology Group; IC, immune cell; PD-L1, programmed death-ligand 1; ULN, upper limit of normal.

      3.2 Efficacy

      Best responses of target lesions are shown in the waterfall plot (Fig. 1A): 15 (14.6%) patients had PR, 43 (41.7%) patients had SD and 32 (31.1%) patients had PD (Table 2, Fig. 1B). The ORR was 14.6% (95% confidence interval [CI], 8.39–22.88) and the DCR was 38.8% (95% CI, 29.39–48.94) (Table 2).
      Fig. 1
      Fig. 1Patient tumour outcomes. (A) Waterfall plot showing maximal reduction in target lesion size from baseline. (B) Swimmer plot showing individual patients' outcomes and time on treatment. For patients with missing discontinuation dates, date of treatment discontinuation has been substituted with the date of last exposure. NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; SLD, sum of longest diameters.
      Table 2Tumour response rates.
      Cohort ACohort BAll patients
      N9211103
      Objective response rate11 (12.0)4 (36.4)15 (14.6)
       95% CI6.12–20.3910.93–69.218.39–22.88
      Complete response0 (0)0 (0)0 (0)
      Partial response11 (12.0)4 (36.4)15 (14.6)
      Stable disease40 (43.5)3 (27.3)43 (41.7)
      Progressive disease28 (30.4)4 (36.4)32 (31.1)
      Disease control rate
      Disease control rate was defined as the confirmed objective response rate plus stable disease at 16 weeks posttreatment.
      34 (37.0)6 (54.5)40 (38.8)
       95% CI27.12–47.6623.38–83.2529.39–48.94
      All data are represented as N (%), unless otherwise specified.
      a Disease control rate was defined as the confirmed objective response rate plus stable disease at 16 weeks posttreatment.
      At the time of primary analysis, 78 (75.7%) patients had an event contributing to PFS, including death (n = 11) and disease progression (n = 67). The median PFS was 3.8 months (95% CI, 3.5–5.7) (Fig. 2A) and the 12-month PFS rate was 16.4% (95% CI, 8.0%–24.7%).
      Fig. 2
      Fig. 2Overall survival and progression-free survival. (A) Progression-free survival of all patients, cohorts A and B. (B) Overall survival of all patients, cohorts A and B. Tick marks indicate patients with censored data. NE, not estimable OS, overall survival; PFS, progression-free survival.
      Median duration of PR was 12.7 months (95% CI, 12.1–NE). Median duration of SD was 3.4 months (95% CI, 2.1–4.7). Median OS was 14.7 months (95% CI, 9.8–NE) (Fig. 2B).
      Forty-two (40.8%) patients were treated with ≥1 post-trial therapy following disease progression; the most common treatments were nivolumab (n = 15; 14.6%), ipilimumab (n = 10; 9.7%) and radiotherapy (n = 5; 4.9%).
      Thirty-four (33.0%) patients died: 33 due to PD (91.7%) and one due to grade 5 treatment-related oesophagitis. Median time to death after last therapy/last exposure was 7.8 months (95% CI, 5.0–11.6).

      3.3 Biomarkers

      Genomic tumour profiling categorised the molecular subtypes: BRAF mutant/rearrangement (n = 8), NF1 mutant (n = 17), RAS mutant (n = 42) and non-mutated BRAF/NF1/RAS triple wild-type (n = 19) (Supplementary Appendix Figure A2).
      Patients with BRAF mutations had higher PD-L1 scores and PD-L1 tumour-infiltrating IC positivity was associated with a longer median PFS (4.6 months versus 2.1 months in PD-L1–positive and PD-L1–negative categories, respectively) (Fig. 3A), with 12/90 patients achieving PR (PD-L1 negative, n = 2; PD-L1 positive, n = 10) (Fig. 3B).
      Fig. 3
      Fig. 3Baseline biomarker characteristics. (A) Progression-free survival categorized by PD-L1 expression in immune cells (PD-L1 ICs). IC0 represents PD-L1 expression <1% (PD-L1 negative); IC1/2/3 represents PD-L1 ≥1% (PD-L1 positive). (B) Objective response rate by PD-L1 expression in immune cells (PD-L1 IC). Percentage and number of responders over total count as labelled. (C) Baseline biomarker characteristics in each melanoma molecular subtype. (D) PD-L1, CD8 and TMB by melanoma molecular subtypes. CD8, cluster of differentiation 8. CR, complete response; IC, immune cell; NA, not assessed; ORR, objective response rate; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PR, partial response; TMB, tumour mutational burden.
      ORR by molecular subtype was 62.5% (5/8) in BRAF mutant/fusion, 5.9% (1/17) in NF1 mutant, 11.9% (5/42) in RAS mutant and 21.1% (4/19) in BRAF/NF1/RAS triple wild-type. The overall mean interferon-gamma expression was similar across the molecular subtypes and ranged between 0.20 and 0.36. TMB was associated with melanoma molecular subtypes, with mean TMB of 6.3 mutations/MB in BRAF/NF1/RAS triple wild-type, 48.38 in NF1 mutant and 17.53 in NRAS mutant subtypes (Fig. 3C and D). Best overall response or PFS showed no differences according to TMB (Supplementary Figure A3), whereas PFS was higher in favour of CD8+ >median versus ≤ median (4.2 months versus 3.7 months) with 11/77 patients achieving a PR (CD8+ >median, n = 6; CD8+ ≤median, n = 5) (Supplementary Figure A4). PD-L1 expression in ICs and CD8+ tumour infiltration was similar across molecular subtypes (Fig. 3D). Differential expression of hallmark cancer gene sets from baseline after single-agent cobimetinib is shown in Supplementary Figure A5.

      3.4 Exposure and safety

      Median atezolizumab exposure was 2.8 months (range, 0.0–20.0 months) and the median number of doses was 7.0 (range, 1.0–38.0). Median cobimetinib exposure was 2.9 months (range, 0.0–18.0). Any-grade adverse events (AEs) were observed in all patients except one, and 99.0% of patients had AEs related to study drugs.
      The most common treatment-related AEs (TRAEs) were diarrhoea (75/103; 72.8%), dermatitis acneiform (57/103; 55.3%) and nausea (52/103; 50.5%) (Table 3). TRAEs of grade ≥3 occurred in 57/103 patients (55.3%). One patient had a grade 5 AE of oesophagitis, which was assessed as treatment related by the investigator. Overall, 22 patients (21.4%) had AEs leading to any treatment discontinuation, including myocarditis (n = 4; 3.9%) and encephalitis (n = 4; 3.9%), and 16 patients (15.5%) had AEs leading to the discontinuation of both atezolizumab and cobimetinib (Table 4). All TRAEs except one case of myocarditis resolved with treatment. Seventy-six (73.8%) patients had ≥1 AE leading to dose reductions/interruptions.
      Table 3Treatment-related adverse events reported in ≥10% of patients (any grade) during the study.
      Treatment-related adverse event, n (%)Cohorts A and B (n = 103)
      Any gradeGrade 1Grade 2Grade 3Grade 4
      Gastrointestinal
       Diarrhoea75 (72.8)36 (35.0)28 (27.2)11 (10.7)0
       Nausea52 (50.5)37 (35.9)14 (13.6)1 (1.0)0
       Vomiting37 (35.9)27 (26.2)8 (7.8)2 (1.9)0
       Constipation31 (30.1)21 (20.4)10 (9.7)00
       Dry mouth13 (12.6)12 (11.7)1 (1.0)00
       Mouth ulceration11 (10.7)8 (7.8)3 (2.9)00
      Skin and subcutaneous tissue disorders
       Dermatitis acneiform57 (55.3)24 (23.3)29 (28.2)3 (2.9)1 (1.0)
       Rash35 (34.0)17 (16.5)11 (10.7)7 (6.8)0 (0.0)
       Pruritus20 (19.4)13 (12.6)7 (6.8)00
      General disorders
       Fatigue49 (47.6)29 (28.2)20 (19.4)00
       Pyrexia38 (36.9)24 (23.3)9 (8.7)5 (4.9)0 (0.0)
       Oedema peripheral18 (17.5)12 (11.7)6 (5.8)00
       Chills13 (12.6)12 (11.7)1 (1.0)00
       Asthenia12 (11.7)9 (8.7)3 (2.9)00
      Metabolism and nutrition disorders
       Decreased appetite22 (21.4)14 (13.6)7 (6.8)1 (1.0)0
      Infections and infestations
       Urinary tract infection13 (12.6)2 (1.9)9 (8.7)2 (1.9)0
      Eye disorders
       MEK inhibitor-associated serious retinopathy12 (11.7)7 (6.8)5 (4.9)00
      Nervous system disorders
       Dizziness13 (12.6)9 (8.7)4 (3.9)00
       Headache11 (10.7)9 (8.7)2 (1.9)00
      Respiratory, thoracic and mediastinal disorders
       Dyspnoea12 (11.7)8 (7.8)2 (1.9)2 (1.9)0
      Blood and lymphatic system disorders
       Anaemia14 (13.6)6 (5.8)6 (5.8)2 (1.9)0
      Investigations26 (25.2)8 (7.8)9 (8.7)9 (8.7)0
       Blood creatine phosphokinase increased
       Aspartate aminotransferase increased14 (13.6)11 (10.7)02 (1.9)1 (1.0)
       Alanine aminotransferase increased11 (10.7)7 (6.8)1 (1.0)3 (2.9)0 (0.0)
      Table 4Adverse events leading to treatment discontinuation.
      Treatment-related adverse event, n (%)AtezolizumabCobimetinibBoth treatments
      Total number of patients with at least one adverse event18 (17.5)20 (19.4)16 (15.5)
      Total number of events192317
      Myocarditis4 (3.9)3 (2.9)3 (2.9)
      Encephalitis4 (3.9)4 (3.9)4 (3.9)
      Pneumonitis2 (1.9)2 (1.9)2 (1.9)
      Acute kidney injury1 (1.0)1 (1.0)1 (1.0)
      Alanine aminotransferase increased1 (1.0)1 (1.0)1 (1.0)
      Amylase increased1 (1.0)00
      Anaemia01 (1.0)0
      Blood creatine phosphokinase increased01 (1.0)0
      Colitis1 (1.0)1 (1.0)1 (1.0)
      Ejection fraction decreased01 (1.0)0
      Encephalopathy1 (1.0)1 (1.0)1 (1.0)
      Hepatitis1 (1.0)1 (1.0)1 (1.0)
      Immune-mediated hepatitis1 (1.0)1 (1.0)1 (1.0)
      Meningitis1 (1.0)1 (1.0)1 (1.0)
      Pruritus01 (1.0)0
      Pyrexia1 (1.0)1 (1.0)1 (1.0)
      Rash01 (1.0)0
      Tachycardia01 (1.0)0
      For frequency counts by preferred term, multiple occurrences of the same AE in one individual are counted only once except for the “Total number of events” row, in which multiple occurrences of the same AE are counted separately.

      4. Discussion

      Results of this study demonstrated limited activity with atezolizumab plus cobimetinib in patients with advanced BRAFV600 wild-type melanoma who had progressed on prior anti‒PD-1 therapy. This was unexpected given the promising preclinical and early phase clinical data suggesting that MEK inhibition has beneficial immunomodulatory effects that may enhance response to ICIs [
      • Boni A.
      • Cogdill A.P.
      • Dang P.
      • Udayakumar D.
      • Njauw C.N.
      • Sloss C.M.
      • et al.
      Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.
      ,
      • Ebert P.J.R.
      • Cheung J.
      • Yang Y.
      • McNamara E.
      • Hong R.
      • Moskalenko M.
      • et al.
      MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade.
      ,
      • Hellmann M.D.
      • Kim T.W.
      • Lee C.B.
      • Goh B.C.
      • Miller W.H.
      • Oh D.Y.
      • et al.
      Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.
      ,
      • Liu L.
      • Mayes P.A.
      • Eastman S.
      • Shi H.
      • Yadavilli S.
      • Zhang T.
      • et al.
      The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4.
      ,
      • Loi S.
      • Dushyanthen S.
      • Beavis P.A.
      • Salgado R.
      • Denkert C.
      • Savas P.
      • et al.
      RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors.
      ,
      • Ribas A.
      • Butler M.
      • Lutzky J.
      • Lawrence D.P.
      • Robert C.
      • Miller W.
      • et al.
      Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma.
      ], and the relatively good prognostic features of our cohort at the time of study entry (ECOG PS, 0–1; prior treatment for brain metastases, 10%; liver metastases, 26%) despite progression on prior anti-PD-1 therapy.
      Results from the current study are consistent with the observations from the phase 3 IMspire170 study, in which combination therapy with cobimetinib plus atezolizumab did not improve PFS versus pembrolizumab in patients with previously untreated BRAFV600 wild-type advanced melanoma [
      • Gogas H.
      • Dréno B.
      • Larkin J.
      • Demidov L.
      • Stroyakovskiy D.
      • Eroglu Z.
      • et al.
      Cobimetinib plus atezolizumab in BRAF(V600) wild-type melanoma: primary results from the randomized phase III IMspire170 study.
      ]. At the time the present phase 1b study was conducted, limited data were available regarding treatment options for patients who progressed following anti–PD-1 therapy, and the results of IMspire170 were not available prior to patient recruitment.
      Previous retrospective studies in melanoma patients who progressed on or after anti–PD-1 therapy demonstrated response rates of up to 16% with ipilimumab monotherapy and up to 31% with ipilimumab plus anti–PD-1 therapy [
      • Zimmer L.
      • Apuri S.
      • Eroglu Z.
      • Kottschade L.A.
      • Forschner A.
      • Gutzmer R.
      • et al.
      Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma.
      ,
      • da Silva I.P.
      • Ahmed T.
      • Reijers I.L.M.
      • Weppler A.M.
      • Warner A.B.
      • Patrinely J.R.
      • et al.
      Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.
      ]. In a recent meta-analysis of 14 studies, the pooled response rate was 8% for ipilimumab monotherapy and 23% for ipilimumab combined with nivolumab [
      • Alrabadi N.N.
      • Abushukair H.M.
      • Ababneh O.E.
      • Syaj S.S.
      • Al-Horani S.S.
      • Qarqash A.A.
      • et al.
      Systematic review and meta-analysis efficacy and safety of immune checkpoint inhibitors in advanced melanoma patients with anti-PD-1 progression: a systematic review and meta-analysis.
      ]. Prospective data from a phase 2 study reported a preliminary response rate of 47% (n = 17) with pembrolizumab plus low-dose ipilimumab in patients with melanoma who progressed on prior anti–PD-1 or non–CTLA-4 combination treatment [
      • Olson D.
      • Luke J.J.
      • Hallmeyer S.
      • Bajaj M.
      • Carll T.
      • Krausz T.
      • et al.
      Phase II trial of pembrolizumab (pembro) plus 1mg/kg ipilimumab (ipi) immediately following progression on anti-PD-1 Ab in melanoma (mel).
      ], with the final results demonstrating a response rate of 31% (n = 67) [
      • Olson D.
      • Luke J.J.
      • Stewart Poklepovic A.
      • Bajaj M.
      • Higgs E.
      • Carll T.C.
      • et al.
      Significant antitumor activity for low-dose ipilimumab (IPI) with pembrolizumab (PEMBRO) immediately following progression on PD1 Ab in melanoma (MEL) in a phase II trial.
      ]. In the present study, treatment with cobimetinib plus atezolizumab showed an ORR of 14.6% and a DCR of 38.8% in patients who had progressed on prior anti‒PD-1 therapy. Although the response rate is relatively low, the patient population was treatment refractory, with 73% of the patients having demonstrated primary resistance to prior ICIs. Moreover, a substantial proportion of patients (58%) had also received prior ipilimumab.
      Of patients who achieved PR (n = 12) in the biomarker evaluable population, most were PD-L1 positive (n = 10). Further, the PD-L1–positive subgroup had a longer median PFS than the PD-L1–negative subgroup (4.6 months versus 2.1 months, respectively). Taken together, these data suggest that combination therapy with cobimetinib and atezolizumab may be more effective in tumours with high PD-L1 expression. RNA sequencing results in cohort B were only available for a limited number of patients at each timepoint, likely due to patients not wanting to undergo repeated biopsies in the setting of disease progression.
      In the biomarker-evaluable population, PD-L1 expression and cluster of differentiation 8 (CD8) tumour infiltration did not differ according to BRAFV600 mutation, NF1 mutation, RAS mutation or triple wild-type status. Consistent with previous findings [
      Cancer Genome Atlas Network
      Genomic classification of cutaneous melanoma.
      ,
      • Johnson D.B.
      • Frampton G.M.
      • Rioth M.J.
      • Yusko E.
      • Xu Y.
      • Guo X.
      • et al.
      Targeted next generation sequencing identifies markers of response to PD-1 blockade.
      ], TMB was associated with melanoma molecular subtypes (BRAF, NF1 or RAS mutants) and was higher in NF1 mutant subtype. Despite the higher TMB in NF1 mutant patients, the ORR was 5.9% and median PFS was 3.5 months, which was lower than all other molecular subtypes. This contrasts with a previous meta-analysis showing that high TMB was associated with better OS and PFS versus low TMB groups in patients who received ICIs [
      • Kim J.Y.
      • Kronbichler A.
      • Eisenhut M.
      • Hong S.H.
      • van der Vliet H.J.
      • Kang J.
      • et al.
      Tumor mutational burden and efficacy of immune checkpoint inhibitors: a systematic review and meta-analysis.
      ]. However, enrolment in our trial was limited to patients with advanced melanoma who had progressed on prior anti–PD-1 therapy and therefore had treatment-resistant tumours irrespective of TMB status.
      Treatment with ipilimumab alone or in combination with anti–PD-1 in patients with metastatic melanoma who were resistant to anti–PD-1 monotherapy was associated with a grade ≥3 AE rate of 21%–33% [
      • da Silva I.P.
      • Ahmed T.
      • Reijers I.L.M.
      • Weppler A.M.
      • Warner A.B.
      • Patrinely J.R.
      • et al.
      Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.
      ,
      • Olson D.
      • Luke J.J.
      • Stewart Poklepovic A.
      • Bajaj M.
      • Higgs E.
      • Carll T.C.
      • et al.
      Significant antitumor activity for low-dose ipilimumab (IPI) with pembrolizumab (PEMBRO) immediately following progression on PD1 Ab in melanoma (MEL) in a phase II trial.
      ,
      • Da Silva I.P.
      • Ahmed T.
      • Lo S.
      • Reijers I.L.M.
      • Weppler A.
      • Warner A.B.
      • et al.
      Ipilimumab (IPI) alone or in combination with anti-PD-1 (IPI+PD1) in patients (pts) with metastatic melanoma (MM) resistant to PD1 monotherapy.
      ]. In the current study, 99% of patients experienced TRAEs with cobimetinib plus atezolizumab, with TRAEs of grade ≥3 in 55% of patients. The combination resulted in one reported treatment-related grade 5 oesophagitis. No new safety signals were identified. Similar to previous reports with this combination (15%–30%) [
      • Hellmann M.D.
      • Kim T.W.
      • Lee C.B.
      • Goh B.C.
      • Miller W.H.
      • Oh D.Y.
      • et al.
      Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.
      ,
      • Eng C.
      • Kim T.W.
      • Bendell J.
      • Argiles G.
      • Tebbutt N.C.
      • Di Bartolomeo M.
      • et al.
      Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.
      ], 21.4% of patients discontinued any study treatment due to AEs. Furthermore, immune-related myocarditis and encephalitis, which are rare but established AEs with ICIs [
      • Palaskas N.
      • Lopez-Mattei J.
      • Durand J.B.
      • Iliescu C.
      • Deswal A.
      Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment.
      ,
      • Dalakas M.C.
      Neurological complications of immune checkpoint inhibitors: what happens when you 'take the brakes off' the immune system.
      ], led to the withdrawal of any study treatment in 3.9% and 2.9% of patients, respectively.

      5. Conclusion

      Cobimetinib plus atezolizumab demonstrated limited activity in patients with advanced BRAFV600 wild-type melanoma who had progressed on or after prior anti‒PD-1 therapy. Efficacy and safety data from this study do not support the use of this combination in these patients. Further research may provide additional insight regarding genomic, molecular and immunological factors underlying these observations.

      Author contributions

      SS: Data curation, writing, review and editing. VA: Supervision, writing, review and editing, provision of data. MGC: Data curation, writing, review and editing, formal analysis. TM: Investigation. ASR: Investigation, writing, review and editing. AMM: Resources, data curation, investigation, writing, review and editing, provision of patients and data. IC: Supervision, investigation, writing, review and editing, medical monitor of the study. LR: Conceptualization, data curation, formal analysis, methodology, writing, review and editing. YS: formal analysis. YY: Conceptualization, data curation, investigation, writing, review and editing. YG: Data curation, formal analysis, investigation, visualization, methodology. CX: Data curation, formal analysis, methodology, writing, review and editing. GVL: Resources, data curation, investigation, project administration, writing, review and editing, provision of patients and data.

      Funding

      This analysis was funded by F. Hoffmann–La Roche Ltd. The study was sponsored by F. Hoffmann–La Roche Ltd and Genentech Inc. The sponsors provided the study drugs and collaborated with academic authors on study design and on data collection, analysis, and interpretation. All authors verified that this study was done according to the protocol and attest to data accuracy and completeness. All authors had full access to all study data. All drafts of the manuscript were prepared together with the authors, with professional writing assistance funded by the sponsor. All authors contributed to revisions and final approval of the manuscript and made the decision to submit the manuscript for publication.

      Availability of data and material

      Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SS reports personal fees and/or grants from AstraZeneca, Bristol Myers Squibb, Genentech, Merck Sharp & Dohme, Pfizer, and Novartis/Advanced Accelerator Applications directly to the institution. VA reports personal fees and/or nonfinancial support from Bristol Myers Squibb, Limbic, Merck, Merck Sharp & Dohme, Nektar, Novartis, Oncosec Medical, Pierre Fabre, QBiotics, and Roche. MGC reports personal fees and/or nonfinancial support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, and Takeda. TM reports institutional funding from Alkermes, Array BioPharma, Checkmate Pharmaceuticals, Exicure, Immunocore, Iovance Biotherapeutics, Moderna, Nektar, Novartis, Oncosec Medical, Regeneron Pharmaceuticals, Replimune Group, Synlogic, and Taiga Biotechnologies. ASR reports no conflicts of interest. AMM reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Pierre Fabre, and QBiotics. IC, LR, YS, YY, YG, and CX report employment and stock ownership with Roche. GVL reports personal fees from Amgen, Array BioPharma, Boehringer Ingelheim International, Bristol Myers Squibb, Hexal AG, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, Pierre Fabre, QBiotics, Regeneron Pharmaceuticals, SkylineDx BV, and Specialised Therapeutics Australia Pty Ltd.

      Acknowledgements

      The authors thank Andres Aguilar for his contributions to the research team activities and data interpretation. Editorial assistance was provided by ApotheCom, San Francisco, CA, USA, and funded by F. Hoffmann–La Roche Ltd.

      Appendix ASupplementary data

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