Abstract
Background
Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors.
Patients and methods
This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival.
Results
Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.
Conclusions
Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.
ClinicalTrials.gov Identifier
NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online).
Keywords: atezolizumab, cobimetinib, metastatic colorectal cancer, non-small-cell lung cancer, melanoma, PD-L1
Key Message
The MEK inhibitor cobimetinib promotes survival of intratumoral tumor-specific T cells and may complement the tumor immune effects of the PD-L1 inhibitor atezolizumab. Combination atezolizumab + cobimetinib was tolerable and showed activity in patients with metastatic cancers, including colorectal cancer, non-small-cell lung cancer, and melanoma, regardless of KRAS/BRAF status.
Introduction
Atezolizumab is a humanized engineered anti-programmed cell death 1 ligand 1 (anti-PD-L1) monoclonal antibody that blocks interactions between PD-L1 and its receptors programmed cell death 1 protein (PD-1) and B7.1, thereby enhancing T-cell mediated anticancer immunity [1–3]. Atezolizumab monotherapy has been approved for metastatic urothelial cancer and non-small-cell lung cancer (NSCLC) [2, 4–9]; however, single-agent anti-PD-L1/PD-1 activity can be limited in some patients. Consequently, immune checkpoint inhibitor therapy in combination with chemotherapy and targeted therapies are being explored in multiple tumor types.
Cobimetinib is a MEK1/MEK2 inhibitor that blocks the MAP kinase pathway and is approved in combination with the BRAF inhibitor vemurafenib for unresectable or metastatic melanoma with a BRAF V600E/K mutation [10]. The MAP kinase pathway is frequently upregulated in many human cancers, including a high percentage of pancreatic, colon, lung, ovarian, breast, and kidney tumors, as a result of activating mutations in upstream signaling proteins, such as EGFR, RAS, and RAF. Clinical studies have revealed that activating mutations in KRAS predict resistance to EGFR-targeted therapy in patients with metastatic colorectal cancer (mCRC) [11], suggesting that inhibition of the MAPK pathway may provide benefit in this setting.
Preclinical models have demonstrated that MEK inhibitors (MEKi) may upregulate major histocompatibility complex (MHC) I expression, increase T-cell infiltration into the tumor, and augment the antitumor activity of PD-1 inhibitors [12, 13]. We therefore sought to evaluate the combination of atezolizumab with a MEKi in patients with multiple tumor types, including mCRC, melanoma, and NSCLC. Here we present results from a phase Ib study of the combination of atezolizumab and cobimetinib in patients with mCRC, melanoma, and NSCLC.
Methods
Study design and treatment
This is a phase I/Ib, global, multicenter, open-label study evaluating the safety and activity of the combination of atezolizumab plus cobimetinib in patients with solid tumors (NCT01988896). The study consisted of a phase I dose-escalation stage and a phase Ib indication-specific expansion stage (supplementary Figure S1, available at Annals of Oncology online).
Dose escalation
In the dose-escalation stage, a fixed dose of atezolizumab 800 mg administered intravenously (IV) every 2 weeks (Q2W) was equivalent to a 15-mg/kg every-3-week weight-based dose and estimated from clinical pharmacokinetic data to provide 95% tumor saturation. Cobimetinib was administered at escalating doses orally (PO) once daily (QD) for 21 consecutive days out of 28 (21/7 dosing schedule). The first treatment cycle was 42 days in duration and consisted of a 14-day atezolizumab run-in followed by a 28-day concomitant dosing period. All subsequent treatment cycles were 28 days (supplementary Figure S2, available at Annals of Oncology online).
Dose escalation of cobimetinib started at 20 mg, followed by 40 mg, and then 60 mg. Escalation was carried out using a 3 + 3 design, with a 28-day window to assess dose-limiting toxicities, and continued until the maximum tolerated or maximum administered dose (MTD or MAD) was defined.
Dose expansion
During stage 2, patients were enrolled in multiple parallel dose-expansion cohorts, including (i) mCRC, (ii) melanoma, (iii) NSCLC, (iv) serial-biopsy cohort of any solid tumor, and (v) serial-biopsy cohort of mCRC (supplementary Figure S2, available at Annals of Oncology online). Approximately 50% of patients in the NSCLC cohort were required to have an activating KRAS mutation and 50% of patients in the melanoma cohort were required to have BRAF-V600 mutation-positive tumors. Patients in the mCRC, melanoma, and NSCLC expansion cohorts were treated with atezolizumab 800 mg IV Q2W plus cobimetinib 60 mg PO QD with the 21/7 dosing schedule.
Patients in the any-solid-tumor serial-biopsy cohort were treated with a 14-day run-in of cobimetinib 60 mg PO QD with atezolizumab 800 mg IV administered on day 15, followed by subsequent 28-day cycles of atezolizumab 800 mg IV Q2W plus cobimetinib 60 mg PO QD with the 21/7 dosing schedule.
Because sustained MEK inhibition during the 21/7 cobimetinib dosing schedule might impair naive T-cell maturation needed to replenish mature effector T cells [12], the mCRC serial-biopsy cohort used a 14/14 schedule to explore whether briefer exposures to cobimetinib and longer breaks would reduce the impact on T-cell maturation. Thus, the first cycle consisted of an initial 14-day run-in of cobimetinib 60 mg PO QD with atezolizumab administered on day 15 and was followed by 28-day cycles of atezolizumab 800 mg IV Q2W with cobimetinib 60 mg PO QD administered on a 14/14 schedule.
Patients enrolled in both serial-biopsy cohorts were required to undergo biopsies on (i) pre-dose on cycle 1, day 1; (ii) between days 10 and 14 of the cobimetinib run-in during cycle 1; and (iii) 4–6 weeks after the first dose of atezolizumab.
This study was conducted in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Protocol (and modification) approval was obtained from an independent ethics committee for each site. All patients gave written informed consent.
Patients
Key inclusion criteria included Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Patients with known or active untreated central nervous system metastases, autoimmune disease, prior therapy with T-cell-modulating agents (e.g. anti-cytotoxic T-lymphocyte associated protein 4, anti-PD-1, anti-PD-L1), or prior intolerance to another MEK inhibitor were excluded. Patients were not selected by PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC).
In the dose-escalation phase, patients had advanced treatment-refractory metastatic or locally advanced solid tumor for which no recognized standard therapy exists. In the dose-expansion cohorts, eligibility was determined by primary tumor and/or molecular status (supplementary Figure S2, available at Annals of Oncology online).
Objectives
The primary objective of the study was to evaluate the safety and tolerability of atezolizumab administered with cobimetinib. The dose-escalation phase was designed to identify the MTD or tolerability at the MAD of cobimetinib plus atezolizumab, and the expansion phase investigated a potential recommended phase II dose and schedule. The secondary objectives included assessing the antitumor activity of atezolizumab plus cobimetinib using investigator-assessed best overall response per RECIST v1.1, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory objectives included the assessment of biomarkers as indicators of antitumor activity or immune modulatory effect.
Assessments
The incidence, nature, and severity of adverse events (AEs) and laboratory abnormalities were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The safety assessable population included all patients who received any amount of atezolizumab.
Tumor response was assessed by investigator at baseline and every 8 weeks thereafter, or as clinically indicated, per RECIST v1.1. Assessable patients included those who received any amount of atezolizumab and had measurable disease at baseline.
Correlative analyses
In patients with mCRC, microsatellite instability (MSI) status was assessed locally, as well as centrally by next-generation sequencing-based scoring or polymerase chain reaction (Foundation Medicine, Inc., Cambridge, MA). Patient tumors were classified as microsatellite stable (MSS), MSI-low, or MSI-high, with MSS and MSI-low grouped together.
KRAS and BRAF mutational status were assessed locally and confirmed retrospectively using the Roche Molecular Diagnostics cobas® mutation assay (Foundation Medicine Inc.; Roche Molecular Diagnostics, Pleasanton, CA).
All patients with available pretreatment biopsy tissue were centrally evaluated for PD-L1 expression on TC and IC using the VENTANA SP142 PD-L1 immunohistochemistry (IHC) assay (Ventana, Tucson, AZ). Patients were categorized by TC/IC 0/1 (<5% cells expressing PD-L1) and TC/IC 2/3 (≥5% PD-L1+ cells).
CD8+ T-cell infiltration was assessed by IHC using the anti-CD8 C8/144B antibody (HistoGeneX, Antwerp, Belgium). MHC I expression was assessed using the anti-MHC I EP1395Y antibody (Novus Biologicals, Centennial, CO). Images of stained tumor sections were analyzed using a computer-aided system by measuring the CD8 marker area in the invasive margin, tumor center, and tumor periphery. P values between pre- and posttreatment were calculated using a student’s paired t-test.
Statistical analysis
The study sample size was not based on explicit power and control of type I error considerations, but was designed to obtain preliminary safety, pharmacokinetic, and pharmacodynamic information. The Clopper–Pearson method was to construct 95% CIs for objective response rate (ORR) estimates. Median OS, PFS, and DOR were estimated using the Kaplan–Meier method, and Brookmeyer–Crowley methodology was used to construct 95% CIs. Event-free rates for OS and PFS were estimated using the Kaplan–Meier method. Statistics were carried out using SAS version 9.4 and SAS JMP version 12.
Results
Patients
Between 27 December 2013 and 9 May 2016, 150 patients were treated with atezolizumab and cobimetinib and are included in the analysis (Table 1). One patient who was treated with cobimetinib during the run-in phase discontinued before receiving atezolizumab and was excluded. As of the clinical data cut date (4 September 2017) median safety follow-up was 4.2 months.
Table 1.
Baseline characteristics
| Stage 1 |
Stage 2 |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| Patients | 20-mg cohort n = 4 | 40-mg cohort n = 4 | 60-mg cohort n = 6 | mCRC n = 59 | NSCLC n = 20 | Melanoma n = 20 | Biopsy n = 16 | mCRC biopsy n = 21 | All patients N = 150 |
| Age, years | |||||||||
| Median | 48.0 | 49.0 | 62.5 | 57.0 | 61.0 | 53.5 | 49.5 | 57.0 | 57.0 |
| Range | 40–75 | 21–71 | 47–75 | 29–81 | 35–79 | 27–83 | 20–71 | 23–79 | 20–83 |
| Sex, % | |||||||||
| Male/female | 100/0 | 50/50 | 67/33 | 49/51 | 50/50 | 35/65 | 31/69 | 76/24 | 51/49 |
| ECOG performance status, % | |||||||||
| 0/1 | 50/50 | 100/0 | 17/83 | 48/52 | 55/45 | 75/25 | 44/56 | 38/62 | 51/49 |
| Race, n (%) | |||||||||
| Asian | 0 | 0 | 0 | 22 (37) | 7 (35) | 7 (35) | 10 (63) | 8 (38) | 54 (36) |
| Black or African American | 0 | 0 | 0 | 0 | 1 (5%) | 0 | 0 | 0 | 1 (0%) |
| White | 4 (100) | 4 (100) | 4 (67) | 37 (63) | 11 (55) | 13 (65) | 6 (38) | 12 (57) | 91 (61) |
| Other/Unknown | 0 | 0 | 2 (33) | 0 | 1 (5) | 0 | 0 | 1 (5) | 4 (3) |
| No. of prior systemic therapies | |||||||||
| Median | 6.5 | 2.5 | 4.0 | 6.0 | 3.0 | 0.5 | 4.0 | 7.0 | 5.0 |
| Range | 3–11 | 1–5 | 2–19 | 2–13 | 0–8 | 0–8 | 0–11 | 1–13 | 0–19 |
| PD-L1 IHC IC score, n (%) | |||||||||
| IC0/I | 1 (25) | 1 (25) | 2 (33) | 32 (54) | 11 (55) | 14 (70) | 13 (81) | 14 (67) | 88 (59) |
| IC2/3 | 0 | 0 | 1 (17) | 4 (7) | 5 (25) | 1 (5) | 1 (6) | 3 (14) | 15 (10) |
| Unknowna | 3 (75) | 3 (75) | 3 (50) | 23 (39) | 4 (20) | 5 (25) | 2 (13) | 4 (19) | 47 (31) |
| PD-L1 IHC TC score, n (%) | |||||||||
| TC0/1 | 1 (25) | 1 (25) | 3 (50) | 36 (61) | 13 (65) | 14 (70) | 12 (75) | 17 (81) | 97 (65) |
| TC2/3 | 0 | 0 | 0 | 0 | 3 (15) | 1 (5) | 2 (13) | 0 | 6 (4) |
| Unknown | 3 (75) | 3 (75) | 3 (50) | 23 (39) | 4 (20) | 5 (25) | 2 (13) | 4 (19) | 47 (31) |
| Tumor microsatellite status, n (%)b | |||||||||
| MSS | 1 (25) | 0 | 0 | 35 (59) | 0 | 0 | 1 (6) | 16 (76) | 53 (35) |
| MSI-low | 0 | 0 | 0 | 7 (12) | 0 | 0 | 0 | 2 (10) | 9 (6) |
| MSI-high | 0 | 0 | 0 | 1 (2) | 0 | 0 | 0 | 1 (5) | 2 (1) |
| Unknown | 3 (75) | 4 (100) | 6 (100) | 16 (27) | 20 (100) | 20 (100) | 15 (94) | 2 (10) | 86 (57) |
| BRAF status, n (%) | |||||||||
| Wild type | 0 | 1 (25) | 2 (33) | 32 (54) | 5 (25) | 10 (50) | 1 (6) | 8 (38) | 59 (39) |
| Mutant | 0 | 0 | 2 (33) | 4 (7) | 5 (25) | 9 (45) | 1 (6) | 1 (5) | 22 (15) |
| Unknown | 4 (100) | 3 (75) | 2 (33) | 23 (39) | 10 (50) | 1 (5) | 14 (88) | 12 (57) | 69 (46) |
| KRAS status, n (%) | |||||||||
| Wild type | 1 (25) | 1 (25) | 1 (17) | 13 (22) | 10 (50) | 0 | 1 (6) | 10 (48) | 37 (25) |
| Mutant | 2 (50) | 0 | 2 (33) | 45 (76) | 9 (45) | 0 | 0 | 11 (52) | 69 (46) |
| Unknown | 1 (25) | 3 (75) | 3 (50) | 1 (2) | 1 (5) | 20 (100) | 15 (94) | 0 | 44 (29) |
Due to insufficient or unevaluable tumor samples.
Based on local or centralized testing.
ECOG, Eastern Cooperative Oncology Group; IC, tumor-infiltrating immune cells; IHC, immunohistochemistry; mCRC, metastatic colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; NSCLC, non-small-cell lung cancer; PD-L1, programmed cell death-ligand 1; TC, tumor cell. IC0/1, <5% IC expressing PD-L1; IC2/3, ≥5% IC expressing PD-L1; TC0/1, <5% TC expressing PD-L1; TC2/3, ≥ 5% TC expressing PD-L1.
Fourteen patients were enrolled in the dose-escalation cohort [including three patients with mCRC, two with melanoma, six with NSCLC, and three with other solid tumors (ovarian, thyroid, and metastatic breast cancer)] and were treated with atezolizumab 800 mg plus increasing doses of cobimetinib. There were four patients in each of the 20- and 40-mg cohorts and six patients in the 60-mg cohort (supplementary Table S1, available at Annals of Oncology online). Five of the patients experienced an event leading to discontinuation of study drug in the 20- and 40-mg cohorts; however, there were no dose-limiting toxicities, and therefore MTD was not reached. An additional 136 patients were enrolled in the dose-expansion cohorts (Table 1).
Pooled safety experience
One hundred and fifty patients were assessable for safety analysis overall. The median (range) duration of safety follow-up across all indications was 4.2 (0.7–40.2) months. The median duration of treatment was 2.5 (0.1–39.6) months for cobimetinib and 3.3 (0–39.8) months for atezolizumab. The most common all-grade treatment-related AE (TRAE) was diarrhea (67%), followed by rash (48%) and fatigue (40%) (Table 2). The incidence of grade 3–4 TRAEs was 44%, with the most common being diarrhea (6%), rash, fatigue, and blood CPK increase (5% each) (supplementary Table S3, available at Annals of Oncology online). Treatment-related serious adverse events included nausea, dyspnea, and pneumonitis (n = 2 each). Seventy-one percent of patients required dose modification or interruption due to an AE, with 15% and 30% discontinuing from atezolizumab and cobimetinib, respectively (Table 2). One patient died of sepsis, which was assessed as related to treatment with atezolizumab. This patient had a medical history of infectious disease (right temporal lobe abscess). Safety was similar across each of the pooled disease-specific indications (supplementary Table S3, available at Annals of Oncology online).
Table 2.
Safety summary
| Dose escalation |
Dose expansion |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Total patients with ≥ 1 AE, n (%) | 20-mg cohort n = 4 | 40-mg cohort n = 4 | 60-mg cohort n = 6 | mCRC n = 59 | NSCLC n = 20 | Melanoma n = 20 | Serial biopsy n = 16 | mCRC serial biopsy n = 21 | All patients N = 150 | |
| Any AE | 4 (100) | 4 (100) | 6 (100) | 58 (98) | 20 (100) | 20 (100) | 16 (100) | 20 (95) | 148 (99) | |
| Grade 3–5 AE | 3 (75) | 3 (75) | 2 (33) | 39 (66) | 14 (70) | 17 (85) | 13 (81) | 14 (67) | 105 (70) | |
| Grade 5 AE | 0 | 0 | 1 (17) | 2 (3) | 0 | 1 (5) | 2 (13) | 0 | 6 (4) | |
| Serious AE | 2 (50) | 1 (25) | 2 (33) | 29 (49) | 11 (55) | 5 (25) | 12 (75) | 7 (33) | 69 (46) | |
| Treatment-related AE | 4 (100) | 4 (100) | 6 (100) | 57 (97) | 19 (95) | 20 (100) | 16 (100) | 20 (95) | 146 (97) | |
| Grade 3–5 treatment-related AE | 1 (25) | 1 (25) | 1 (17) | 25 (42) | 11 (55) | 12 (60) | 9 (56) | 7 (33) | 67 (45) | |
| Atezolizumab treatment-related AE | 4 (100) | 4 (100) | 3 (50) | 47 (80) | 14 (70) | 19 (95) | 12 (75) | 14 (67) | 117 (78) | |
| Cobimetinib treatment-related AE | 4 (100) | 4 (100) | 6 (100) | 57 (97) | 18 (90) | 20 (100) | 15 (94) | 20 (95) | 144 (96) | |
| AE leading to withdrawal from atezolizumab | 0 | 1 (25) | 0 | 7 (12) | 3 (15) | 4 (20) | 5 (31) | 3 (14) | 23 (15) | |
| AE leading to withdrawal from cobimetinib | 2 (50) | 2 (50) | 0 | 15 (25) | 9 (45) | 6 (30) | 8 (50) | 3 (14) | 45 (30) | |
| AE leading to any drug dose modification or interruption | 1 (25) | 3 (75) | 4 (67) | 41 (70) | 17 (85) | 17 (85) | 12 (75) | 12 (57) | 107 (71) | |
AE, adverse event; mCRC, metastatic colorectal cancer; NSCLC, non-small-cell lung cancer.
Pooled clinical activity analysis by disease
Across cohorts, 84 patients with mCRC, 22 with melanoma, 28 with NSCLC, and 16 with other cancers were treated (supplementary Table S2, available at Annals of Oncology online). Patients had received a median (range) of 5 (0–19) prior therapies. Most patients had low PD-L1 expression on TC and/or IC (65%/59% TC/IC 0/1, 4%/10% TC/IC 2/3, 31% unknown). The overall median (range) duration of follow-up for each cohort was 17.0 (0.5–33.8) months for mCRC, 32.7 (2.1–33.9) months for melanoma, and 30.1 (1.4–39.8) months for NSCLC (Table 3). ORR was 8% (7/84) in patients with mCRC, 41% (9/22) in patients with melanoma, 18% (5/28) in patients with NSCLC, and 19% (3/16) in patients with other tumors (ovarian cancer, clear-cell sarcoma, and renal cell carcinoma). The changes in tumor burden for each tumor type are shown in Figure 1. The median DOR was 14.3 months in mCRC and not estimable in the melanoma and NSCLC cohorts (Table 3). The 12-month PFS and OS rates were 11% and 43% for mCRC, 50% and 85% for melanoma, and 29% and 57% for NSCLC, respectively (Table 3). Median OS was 9.8 months for mCRC, not estimable for melanoma, and 13.2 months for NSCLC.
Table 3.
Pooled clinical activity of atezolizumab plus cobimetinib
| mCRC n = 84 | Melanoma n = 22 | NSCLC n = 28 | |
|---|---|---|---|
| Best overall responsea | |||
| ORRb, n (%) [95% CI] | 7 (8) [3–16] | 9 (41) [21–64] | 5 (18) [6–37] |
| CR, n (%) | 0 | 0 | 1 (4) |
| PR, n (%) | 7 (8) | 9 (41) | 4 (14) |
| SD, n (%) | 19 (23) | 7 (32) | 12 (43) |
| PD, n (%) | 51 (61) | 6 (27) | 6 (21) |
| Missing/unevaluable, n (%) | 7 (8) | 0 | 5 (18) |
| Duration of response | |||
| Median (range), months | 14.3 (5.4–31.4+) | NE (12.9–31.1+) | NE (10.7–33.1+) |
| Progression-free survival | |||
| Median (95% CI), months | 1.9 (1.8–2.3) | 13.3c (2.8–NE) | 5.8 (2.7–9.2) |
| 12-month PFS rate (95% CI), % | 11 (4–18) | 50 (29–71) | 29 (11–47) |
| Overall survival | |||
| Median (95% CI), months | 9.8 (6.2–14.1) | NE (18.7–NE) | 13.2 (9.2–NE) |
| 12-month rate (95% CI), % | 43 (32–55) | 85 (69–100) | 57 (38–77) |
| Duration of survival follow-upd | |||
| Median (range), months | 17.0 (0.5–33.8) | 32.7 (2.1+–33.9) | 30.1 (1.4+–39.8) |
In 16 patients with other solid tumors ORR was 19% (n = 3, [95% CI, 4–46]), all of them PRs. 44% (n = 7) had SD and 25% (n = 4) had PD. Tumor types included: nasopharyngeal cancer (n = 5), ovarian cancer (n = 2), bile duct cancer, bladder cancer, metastatic breast cancer, clear-cell soft tissue sarcoma, endometrial cancer, leiomyosarcoma, malignant neoplasm of the ampulla of Vater, papillary renal cell carcinoma, and thyroid cancer (n = 1 each).
Investigator-assessed objective response per RECIST v1.1, confirmed by repeat assessment ≥4 weeks after initial documentation.
Median PFS for non-ocular melanoma was 15.7 months (n = 20 [95% CI, 2.8–NE]).
Duration of survival follow-up is defined as the time from start of treatment to event based on Kaplan–Meier estimates.
CR, complete response; mCRC, metastatic colorectal cancer; NE, not estimable; NSCLC, non-small-cell lung cancer; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. + indicates a censored assessment.
Figure 1.
Change in tumor burden by (A) MSI status and best response in patients with mCRC, (B) best response in patients with NSCLC, (C) best response in patients with melanoma, and (D) best response in patients with other tumors. mCRC, metastatic colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stability; NSCLC, non-small-cell lung cancer; SLD, sum of largest tumor diameters.
Pooled efficacy analysis by molecular status
Microsatellite stability
Among patients with mCRC, 64 of 84 (76%) were tested for MSI status. Two patients (2%) in the mCRC cohort were MSI-high and 62 (74%) were MSI-low or MSS. The ORR was 50% (1/2) in those with MSI-high mCRC, 10% (6/62) in those with MSI-low/MSS, and 0% (0/20) in unknown MS.
KRAS and BRAF
Fifty-seven patients (68%) with mCRC had KRAS mutations (supplementary Table S2, available at Annals of Oncology online). Their ORR was 9% (5/57) compared with 8% (2/25) in patients with KRAS wild-type disease (supplementary Table S4, available at Annals of Oncology online). One patient in each group had an ongoing response at study end (supplementary Figure S3, available at Annals of Oncology online). PFS and OS by KRAS mutation status in patients with mCRC and NSCLC are shown in supplementary Figure S4 (available at Annals of Oncology online).
In NSCLC, 12 patients (43%) had tumors with KRAS mutations, and 12 (43%) had wild-type tumors. Among patients with NSCLC, the ORR was 1 in 12 (8%) in the KRAS-mutant group and 4 in 12 (33%) in those with KRAS wild-type tumors (supplementary Table S4, available at Annals of Oncology online).
In melanoma, BRAF mutations were identified in 10 patients (46%). ORR was 40% (4/10) in those with a BRAF mutation and 50% (5/10) in those with BRAF wild-type disease. Three patients with BRAF-mutant tumors and two with wild-type tumors had ongoing responses (supplementary Figure S5, available at Annals of Oncology online).
Biomarkers
CD8+ T-cell infiltration and MHC I levels were analyzed in pretreatment and on-treatment tumor samples to explore whether clinical results would recapitulate increases in CD8+ T-cell infiltration and MHC I levels observed in preclinical models of MEKi [12, 13]. In the all-solid-tumor serial-biopsy cohort, an increase in CD8+ T-cell infiltration with cobimetinib monotherapy was observed in 79% of evaluated patients (11/14, P = 0.02 for pretreatment versus on-treatment), although the low response rate (19%, n = 3) limits the interpretation of these results. MHC I increased in 43% (6/11) of patients (P = 0.2, not significant) (supplementary Figure S5, available at Annals of Oncology online).
Representative CD8 and MHC I IHC images from archival/baseline and on-treatment tumor samples are shown for the patient with clear-cell sarcoma who had a partial response (supplementary Figure S6, available at Annals of Oncology online). Compared with levels before treatment, the percentage of CD8+ T cells increased from 0.1% to 12.2% and the MHC I H-score increased from 60 to 300 after starting the cobimetinib run-in. Upon adding atezolizumab to cobimetinib and performing a repeat biopsy, the percentage of CD8+ T cells further increased to 50.0% and the H-score for MHC I expression remained at the maximum of 300.
Discussion
In heavily pretreated patients with chemotherapy-refractory mCRC, melanoma and NSCLC AEs experienced with atezolizumab plus cobimetinib were consistent with those observed with single agents [2, 14] and no unexpected AEs were observed; however, grade 3–4 TRAEs occurred in 44% of patients, and 15% and 30% of patients discontinued atezolizumab and cobimetinib, respectively. Approximately 70% found the combination intolerable and required discontinuation or dose reduction, raising concerns about whether patients would be able stay on therapy long enough to maintain antitumor responses. Additional dosing approaches, such as pulse dosing of MEK inhibition, may be tried in the future to optimize the balance between tolerability and depth of pathway inhibition.
Some durable responses were seen in patients who received atezolizumab plus cobimetinib. In patients with NSCLC or melanoma, although activity was seen, the current results do not suggest a clear benefit with atezolizumab plus cobimetinib versus atezolizumab monotherapy in this PD-L1/PD-1–naive population. The ORR in patients with NSCLC and melanoma were similar to previous data with atezolizumab monotherapy and other PD-L1/PD-1 inhibitors in patients with these diseases [4, 15]. Because of the small sample sizes, no association with efficacy and PD-L1 expression could be identified. Overall, in each disease, there was no evident enrichment in ORR or PFS in patients with KRAS-mutant tumors versus wild-type tumors, except in patients with NSCLC; among these patients there was a trend toward higher ORR in those with wild-type disease.
At last, however, it was notable that the combination of atezolizumab plus cobimetinib demonstrated antitumor activity in patients with MSI-low/MSS mCRC, whereas single-agent anti-PD-L1/PD-1 therapies have historically shown minimal activity [16]. Evaluation of paired pretreatment and on-treatment biopsies revealed an increase in CD8+ T-cell infiltration with atezolizumab + cobimetinib, supporting preclinical observations of a complementary effect of MEKi and anti-PD-L1 activity [13, 14, 17]. Therefore, increasing CD8+ T-cell infiltration may be necessary but not sufficient for clinical response, and additional immunosuppressive mechanisms may be occurring that also need to be overcome.
Based on these results, atezolizumab plus cobimetinib was subsequently tested in the IMblaze370 phase III study examining patients with MSS CRC tumors. Unfortunately, although atezolizumab plus cobimetinib showed a trend toward improved OS versus atezolizumab monotherapy, efficacy with the combination was not superior to regorafenib [18]. Therefore, despite the favorable pharmacodynamic effects of cobimetinib on the tumor microenvironment, atezolizumab plus cobimetinib was not sufficient to overcome resistance to cancer immunotherapies in patients with MSS mCRC. Analysis of this combination continues in patients with melanoma in the phase III study IMspire170 (NCT03273153), which is evaluating atezolizumab plus cobimetinib versus pembrolizumab in patients with previously untreated BRAF wild-type metastatic or unresectable locally advanced melanoma and may further inform the histology-dependent effects of this combination on the tumor immune environment.
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Supplementary Material
Acknowledgements
The authors acknowledge Wei Yu and the development staff at Genentech and F. Hoffmann-La Roche for contributions to data analyses. Medical writing assistance was provided by Christopher Lum, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.
Funding
This work was supported by F. Hoffmann-La Roche Ltd./Genentech, Inc., a member of the Roche Group (no grant number is applicable). All authors had access to the study data and confirm data accuracy and completeness.
Disclosure
MDH receives research funding from Bristol-Myers Squibb (BMS); is a paid consultant to Merck, BMS, AstraZeneca, Genentech/Roche, Janssen, Nektar, Syndax, Mirati, and Shattuck Labs; and receives travel support/honoraria from AstraZeneca and BMS; also, Memorial Sloan Kettering Cancer Center has filed a patent that is related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics, Inc. T-WK has received research grants from AstraZeneca, Pfizer, and Merck Serono. CBL has served as chair of the data and safety monitoring board for Delcath. B-CG has received research grants from Bayer Healthcare, Otsuka Pharmaceuticals, MSD, and Roche/Genentech. WHM has received consulting fees from BMS, Merck, Roche, Novartis, Amgen, and GSK, received institutional support from BMS, Pfizer, Amgen, Roche, Medimmune, Merck, Novartis, AstraZeneca, and Methylgene; and received speaking honoraria from BMS, Merck, Roche, Novartis, and GSK. D-YO has received research grants from AstraZeneca and consulting fees from Merck Serono. RJ has received institutional research support from BMS, Pfizer, Roche/Genentech, AstraZeneca, MedImmune, GSK, and Novartis. C-EC has declared no conflicts of interest. LQMC has received consulting fees and institutional research support from Genentech. JFG has received consulting fees or honoraria from BMS, Novartis, Pfizer, Merck, Roche/Genentech, Loxo, Incyte, Array, Agios, Regeneron, Amgen, Oncorus, Jounce, and ARIAD/Takeda; institutional research support from BMS, Novartis, Merck, Roche/Genentech, Blueprint, Array, Jounce, Adaptimmune, Alexo, and Tesaro; and research grants from Genentech, ARIAD/Takeda, and Novartis. JD has been an advisory board member for Lilly, Bionomics, Eisai, BeiGene, and Ignyta; received honoraria from Lilly, Bionomics, and Eisai; received grants or research support from Genentech/Roche, GSK, Novartis, Bionomics, MedImmune, BeiGene, Lilly, and BMS; and received funding for conducting the parent study and editorial support from F. Hoffmann-La Roche. BJS has received consulting fees or honoraria from Roche/Genentech, Pfizer, Novartis, AstraZeneca, Merck, BMS, and Loxo Oncology. MDT is an employee of Genentech. BP is an employee of Roche. PF was an employee of Roche/Genentech during the time of the study, is currently an employee of Beigene, and owns stock in Roche and Exelixis. MJW, GH, and EC are employees and shareholders of Roche/Genentech. Y-JB has received consulting fees from AstraZeneca, Novartis, Genentech/Roche, MSD, Bayer, BMS, Eli Lilly, Merck Serono, Taiho, Daiichi-Sankyo, Astellas, BeiGene, Green Cross, Samyang Biopharm, and Hanmi, and received research grants from AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serono, Bayer, GSK, BMS, Pfizer, Eli Lilly, Boehringer-Ingelheim, MacroGenics, Boston Biomedical, Five Prime, CKD Pharma, Ono, Taiho, Takeda, BeiGene, Green Cross, Curis, Daiichi-Sankyo, and Astellas. LLS has received consulting fees from Merck, Pfizer, Celgene, AstraZeneca/Medimmune, Morphosys, Roche, GeneSeeq, Loxo, Oncorus, and Symphogen; received research grants from Novartis, BMS, Pfizer, Boehringer-Ingelheim, Regeneron, GSK, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, and Intensity Therapeutics; and is an Agios stockholder through her spouse. JB has received institutional support from the study sponsor, Roche/Genentech. JB’s institution has received consulting fees from BMS, Roche, Merck, Taiho Oncology, Amgen, Genentech, Merrimack, Celgene, MedImmune, Seattle Genetics, Daiichi-Sankyo, Janssen, Translational Drug Development, Five Prime Therapeutics, Moderna Therapeutics, Tolero, Evelo Biosciences, Arrys Therapeutics, Forma Therapeutics, Tanabe Research Laboratories, BeiGene, Continuum Clinical, and Cerulean. JB served as principal investigator and received institutional support for the conduct of clinical trials from AbbVie, AstraZeneca, EMD Serono, Ipsen Biopharma, Incyte, Novartis, Eisai, Pfizer, Millennium, Imclone, Boston Biomedical, CALGB, Acerta Pharma, Lilly, Gilead Sciences, Leap Therapeutics, Macrogenics, OncoMed Pharmaceuticals, Takeda, Rgenix, Novocure, Blueprint Medicine, Array Biopharma, ARMO Biosciences, Agios, and Merus, NV. JB’s institution, Sarah Cannon Research Institute, conducts clinical trials and performs consulting services for several hundred companies; JB was personally involved with those listed here.
References
- 1. Chen DS, Irving BA, Hodi FS.. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 2012; 18(24): 6580–6587. [DOI] [PubMed] [Google Scholar]
- 2. Herbst RS, Soria JC, Kowanetz M. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515(7528): 563–567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Chen DS, Mellman I.. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013; 39(1): 1–10. [DOI] [PubMed] [Google Scholar]
- 4. Fehrenbacher L, Spira A, Ballinger M. 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. Lancet 2016; 387(10030): 1837–1846. [DOI] [PubMed] [Google Scholar]
- 5. Powles T, Eder JP, Fine GD. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014; 515(7528): 558–562. [DOI] [PubMed] [Google Scholar]
- 6. McDermott DF, Sosman JA, Sznol M. et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 2016; 34(8): 833–842. [DOI] [PubMed] [Google Scholar]
- 7. Balar AV, Galsky MD, Rosenberg JE. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389(10064): 67–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Rittmeyer A, Barlesi F, Waterkamp D. et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017; 389(10066): 255–265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Rosenberg JE, Hoffman-Censits J, Powles T. 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. Lancet 2016; 387(10031): 1909–1920. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Cotellic (cobetinib) [package insert]. South San Francisco, CA: Genentech, Inc. 2018.
- 11. Misale S, Yaeger R, Hobor S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486(7404): 532–536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Rosen LS, LoRusso P, Ma WW. et al. A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Invest New Drugs 2016; 34(5): 604–613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Ebert PJ, Cheung J, Yang Y. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 2016; 44(3): 609–621. [DOI] [PubMed] [Google Scholar]
- 14. Liu L, Mayes PA, Eastman S. 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. Clin Cancer Res 2015; 21(7): 1639–1651. [DOI] [PubMed] [Google Scholar]
- 15. Fehrenbacher L, von Pawel J, Park K. et al. Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab vs docetaxel in patients with previously treated advanced non-small cell lung cancer. J Thorac Oncol 2018; 2018; 13(8): 1156–1170. [DOI] [PubMed] [Google Scholar]
- 16. Le DT, Uram JN, Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372(26): 2509–2520. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Chen D, Heath V, O'Garra A. et al. Sustained activation of the raf-MEK-ERK pathway elicits cytokine unresponsiveness in T cells. J Immunol 1999; 163: 5796–5805. [PubMed] [Google Scholar]
- 18. Bendell J, Ciardiello F, Tabernero J. et al. Efficacy and safety results from IMblaze370, a randomised phase III study comparing atezolizumab+cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol 2018; 29(Suppl 5): [abstract LBA004]. [Google Scholar]
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