Safety of Nivolumab plus Low‐Dose Ipilimumab in Previously Treated Microsatellite Instability‐High/Mismatch Repair‐Deficient Metastatic Colorectal Cancer

Abstract

Background

Early detection and management of treatment‐related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low‐dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12‐month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) metastatic colorectal cancer (mCRC). In‐depth safety and additional efficacy outcomes from CheckMate 142 are presented.

Materials and Methods

Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune‐mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune‐modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs.

Results

Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2–12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5–9.0 weeks). IMMs were used to manage sTRAEs in 22%–56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12‐month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%).

Conclusion

The benefit‐risk profile of nivolumab plus low‐dose ipilimumab provides a promising treatment option for patients with previously treated MSI‐H/dMMR mCRC.

Implications for Practice

Nivolumab (NIVO) plus low‐dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment‐related adverse events (sTRAEs) occurred early, were managed using evidence‐based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune‐modulating medications. The benefit‐risk profile of NIVO + low‐dose IPI provides a promising treatment option for MSI‐H/dMMR mCRC.

Abstract

摘要

背景?在接受免疫检查点抑制剂治疗的患者中?早期发现和管理治疗相关不良事件 (TRAE) 可改善预后?在 CheckMate 142 研究中?纳武单抗 (3 mg/kg) 联合低剂量易普利姆玛单抗 (1 mg/kg) 可提供持久的临床疗效 [客观反应率 (ORR)为 55%?未达到中位反应持续时间?12 个月的总生存(OS)率为 85%]?且对于既往已接受微卫星不稳定性高/错配修复缺陷(MSI‐H/dMMR)转移性结直肠癌 (mCRC) 治疗的患者具有可控的安全特性?此外?还介绍了 CheckMate 142 的深度安全性及其他疗效?

材料和方法?安全性评估包括TRAE发生频率?选择性TRAE (sTRAE) 及免疫介导型不良事件的发生率?发生时间 (TTO)?消退时间 (TTR)?免疫调节药物 (IMM) 的使用?剂量延迟?恢复治疗后出现sTRAE?疗效评估包括对sTRAE伴有或不伴IMM的患者及不伴sTRAE的患者的ORR和生存率进行分析?

结果?在 119 名患者中?25%?23%?19%?5%?5% 及 29% 的患者分别出现了内分泌系统?胃肠?肝脏?肺?肾脏或皮肤方面的sTRAE?多数 (57%) 属于 1/2 级?sTRAE发生于早期(中位TTO?5.2–12.6 周)?多数(超过 71%)患者的非内分泌系统sTRAE消退(中位TTR?1.5–9.0 周)?22%–56% 的患者使用IMM治疗sTRAE(多数均消退)?在由于sTRAE而导致剂量延迟的患者中?29 例中有 25 例恢复了治疗?对于伴有或不伴sTRAE的患者?在ORR(57% vs. 52%)和 12 个月的OS率(93% vs. 75%)方面相差无几?经观察发现?无论IMM使用与否?伴有或不伴sTRAE的患者均取得了类似的疗效(ORR 52% vs. 57%?OS率 87% vs. 82%)?

结论?根据对纳武单抗联合低剂量易普利姆玛单抗的疗效‐风险分析?此种疗法将有望成为既往已接受MSI‐H/dMMR mCRC治疗者的首选治疗方案?

实践意义:纳武单抗 (NIVO) 联合低剂量 (1 mg/kg) 易普利姆玛单抗 (IPI) 疗法获得了美国食品和药品管理局的批准?可用于患微卫星不稳定高/错配修复缺陷 (MSI‐H/dMMR) 转移性结直肠癌 (mCRC) 且在接受氟尿嘧啶?奥沙利铂及伊立替康的治疗后病情恶化(基于 CheckMate 142 研究的结果)的患者?在此项安全性分析中?大多数选择性治疗相关不良事件 (sTRAE) 均发生于早期?在采用循证治疗方法进行治疗后消退?无论是否同时使用免疫调节药物?伴有或不伴sTRAE的患者均取得了类似的疗效?根据对NIVO联合低剂量IPI的疗效‐风险分析?此种疗法将有望成为MSI‐H/dMMR mCRC的首选治疗方案

Introduction

Colorectal cancer (CRC) is the fifth leading cause of cancer‐related death worldwide, and by 2030, its global incidence is expected to increase by 60% [1, 2]. In the U.S., CRC is the third most common cancer, and incidence rates are increasing in adults less than 55 years [3, 4]. Outlook remains poor for patients with metastatic CRC (mCRC), with a 5‐year survival rate of 14% [3]. Patients with microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) mCRC benefit less from conventional chemotherapy than those with microsatellite stable/mismatch repair‐proficient mCRC [5–8]; conversely, MSI‐H/dMMR is a predictive marker of response to treatment with anti‐programmed death (PD)‐1 checkpoint inhibitor therapy [9–12].

Preclinical evidence has demonstrated that PD‐1 and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) checkpoint inhibitors, such as nivolumab and ipilimumab, respectively, act synergistically and promote an antitumor immune response by distinct yet complementary mechanisms [13]. Nivolumab is a human monoclonal antibody inhibitor of PD‐1 that received accelerated U.S. Food and Drug Administration (FDA) approval as a monotherapy or in combination with low‐dose ipilimumab for patients with MSI‐H or dMMR mCRC who progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan [14, 15]. Combined nivolumab and ipilimumab‐mediated blockade resulted in enhanced T‐cell function that was greater than either antibody alone and improved antitumor responses in patients with metastatic melanoma [16]. Currently, dual immune checkpoint blockade with PD‐1 and CTLA‐4 inhibitors is being evaluated for a wide range of tumors [17].

In the combination cohort of CheckMate 142 trial, patients with previously treated MSI‐H/dMMR mCRC were treated with nivolumab (3 mg/kg) plus low‐dose (1 mg/kg) ipilimumab every 3 weeks (Q3W), followed by nivolumab monotherapy every 2 weeks (Q2W) until disease progression; discontinuation because of toxicity, death, or withdrawal of consent; or study end [18]. After a median follow‐up of 13.4 months, this combination provided durable clinical benefit demonstrated by a high objective response rate (ORR; 55%) with the median duration of response (DOR) not reached and disease control (≥12 weeks) in 80% of patients, encouraging survival (12‐month progression‐free survival [PFS] and overall survival [OS] rates of 71% and 85%, respectively), and manageable safety with a low discontinuation rate because of an adverse event (AE) related to the study drug (13%) [18].

Because of their unique mechanisms of action, immune checkpoint inhibitors are associated with AEs that differ from chemotherapy‐related AEs. These immune‐related AEs often affect the skin, gastrointestinal (GI), pulmonary, renal, endocrine, and hepatic systems. Early AE detection and proper management, including use of systemic corticosteroids when indicated, may improve outcomes in patients receiving checkpoint inhibitor therapy [19]. Here, we provide an in‐depth analysis of the safety profile of nivolumab plus low‐dose ipilimumab in previously treated patients with MSI‐H/dMMR mCRC from CheckMate 142, including characteristics and management of select treatment‐related adverse events (sTRAEs), and efficacy outcomes in patients who experienced sTRAEs.

Materials and Methods

Study Design

CheckMate 142 is a phase II, multicohort, multicenter, open‐label trial (NCT02060188). Details of the nivolumab plus low‐dose ipilimumab cohort in previously treated patients with MSI‐H/dMMR mCRC have been published [18]. Briefly, patients from eight countries (28 sites) received nivolumab 3 mg/kg and low‐dose ipilimumab 1 mg/kg once Q3W for four doses followed by nivolumab 3 mg/kg Q2W until disease progression; discontinuation because of toxicity, death, or withdrawal of consent; or study end [18]. The primary endpoint was investigator‐assessed ORR per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). The secondary endpoints included ORR per blinded independent central review (BICR) and disease control rate (DCR). Other key endpoints included PFS (investigator assessment and BICR), OS, patient‐reported outcomes, and safety and tolerability [18].

Patients

Adults with histologically confirmed recurrent or metastatic CRC classified as dMMR and/or MSI‐H (per local standards) and whose disease had progressed on or after or were intolerant of at least one prior therapy that included a fluoropyrimidine, oxaliplatin, or irinotecan were included in the trial. Eligible patients had an Eastern Cooperative Oncology Group performance score ≤1 and measurable disease per RECIST version 1.1 [18]. Patients who had autoimmune disease (active, known, or suspected); conditions requiring corticosteroids or other immunosuppressive medication (≤14 days before first dose); other serious or uncontrolled medical disorders; active brain or leptomeningeal metastases; or prior malignancy within the previous 3 years except for cured select localized cancers were excluded. Additional exclusion criteria included prior treatment with an anti‐PD‐1, anti‐PD‐ligand 1 (L1)/PD‐L2, anti‐CTLA‐4, or any other agents targeting the T‐cell costimulation or immune checkpoint pathways [18].

Safety Assessments

Safety assessments included incidence of TRAEs, TRAEs leading to discontinuation or delay, and incidence and management of sTRAEs and immune‐mediated adverse events (IMAEs). sTRAEs and IMAEs were predefined in the protocol. sTRAEs were defined as AEs of special clinical interest meeting defined criteria that were grouped by specific category (e.g., endocrine, GI, hepatic, pulmonary, renal, and skin events) and had a potential immunologic etiology. IMAEs were defined as specific events that included diarrhea and colitis, hepatitis, pneumonitis, nephritis and renal dysfunction, rash, and endocrine events (adrenal insufficiency, hypophysitis, hypothyroidism/thyroiditis, hyperthyroidism, and diabetes mellitus). All safety assessments were based on the clinical assessment of the investigator. Safety was evaluated between the first dose and 30 days after the last dose of study therapy. IMAE analyses were conducted regardless of causality within 100 days of the last dose and limited to patients who received immune‐modulating medication (IMM), with the exception of endocrine events, which were included in the analysis regardless of treatment. IMMs, including corticosteroids and immunosuppressive agents, were used to manage sTRAEs and IMAEs per protocol‐specified algorithms [20]. Time to onset of any grade sTRAEs or IMAEs was defined as the time between the day of the first dose of study treatment and the onset date of the earliest AE. Time to resolution of sTRAEs or IMAEs was defined as the longest time from onset to complete resolution or improvement to baseline grade. sTRAEs leading to dose delay, patients resuming nivolumab plus low‐dose ipilimumab treatment after dose delay, and sTRAEs after resuming therapy were recorded. Treatment delays up to 6 weeks from the last dose were allowed (supplemental online Table 1). Patients were allowed to resume treatment when the TRAE resolved to grade ≤1 or to baseline values, with some exceptions (supplemental online Table 1).

Efficacy Assessments

Efficacy assessments included ORR (defined as number of patients with complete response [CR] + partial response [PR] divided by the number of treated patients), best overall response (CR, PR, stable disease [SD], and progressive disease), DCR (defined as number of patients with CR + PR + SD ≥12 weeks divided by the number of treated patients), OS, and PFS.

Study Oversight

The study protocol and amendments were approved by the institutional review board or independent ethics committee at each participating center. CheckMate 142 was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and patients provided written informed consent before enrollment [18].

Statistical Analysis

Analyses of patient characteristics and safety data were descriptive; sTRAEs were tabulated by frequency and severity and by system organ class and preferred term. OS, PFS, and DOR were estimated using the Kaplan‐Meier method. Medians and corresponding 95% confidence intervals (CIs) were determined with Brookmeyer and Crowley methods; 95% CIs were constructed by means of a log‐log transformation. Landmark survival rates (i.e., OS or PFS at 12 months) were derived using the Kaplan‐Meier method, and corresponding CIs were estimated based on the Greenwood formula for variance derivation with log‐log transformation applied to the survivor function. Statistical analyses were performed using SAS software (SAS Institute, Cary, NC) [18].

Results

Patients and Exposure

A total of 119 patients were treated. At the data cutoff (July 2017), the median follow‐up (time from first dose to data cutoff) was 13.4 months (range, 9–25 months), with 63% of patients still receiving treatment [18]. The demographics and baseline disease characteristics for these patients have been published previously. Briefly, the majority of patients (68%) were aged <65 years and 76% had received ≥2 prior lines of systemic therapy [18]. Eighty‐six percent of patients received all four doses of nivolumab plus low‐dose ipilimumab. The median number of nivolumab doses received was 24 (1–55), and the median number of ipilimumab doses was 4 (1–4).

Safety

Overall, 73% of patients reported TRAEs and 32% reported grade 3 or 4 TRAEs. The most common any grade TRAEs were diarrhea (22%), fatigue (18%), and pruritus (17%) [18]. In all, 13% of patients discontinued treatment because of TRAEs, the most common of which were autoimmune hepatitis (2%) and acute kidney injury (2%) [18]. A total of 23 patients (19%) died within 100 days of the last dose of study therapy. The primary reason for death was disease progression and no deaths were attributed to study drug‐related toxicity.

sTRAEs are summarized in Table 1. The majority of sTRAEs were grade 1 or 2, occurring in 38 patients, and no grade 5 sTRAEs were reported (Table 1) [18]. The most common sTRAEs of any grade were skin related (29%), whereas the most common grade 3 or 4 sTRAEs were hepatic (11%; Table 1). Grade 3 or 4 sTRAEs reported in at least 3% of patients included elevated levels of aspartate aminotransferase (AST; 8%), increased alanine aminotransferase (7%), increased transaminases (3%), and colitis (3%). Most sTRAEs of any grade occurred early, with median time to onset within the first 12 weeks of therapy (Fig. 1A, 1B). At data cutoff, management with previously published protocol‐specific algorithms [20] resulted in the resolution of nonendocrine sTRAEs in the majority of patients (GI 96%, hepatic 74%, pulmonary 83%, renal 83%, and skin 71%; Fig. 1C), and only a small number of patients had unresolved sTRAEs (GI, n = 2; hepatic, n = 6; pulmonary, n = 1; renal, n = 1; and skin, n = 10). Endocrine sTRAEs resolved in 40% (n = 12) of patients [18]. Six patients with unresolved endocrine sTRAEs required hormone replacement therapy. Overall, median time to nonendocrine sTRAE resolution ranged from 1.5 to 9 weeks [18] (Fig. 1C).

Overall, 22%–56% of patients with sTRAEs were treated with IMMs, including immunosuppressive agents or systemic corticosteroids, depending on organ‐specific sTRAE category, as specified by protocol‐specific algorithms [18, 20]. The most common sTRAE category for which patients received IMMs was skin, in which 19 of 34 patients (56%) with a sTRAE received IMMs, primarily topical corticosteroids (15 of 19 patients; 79%). Across all sTRAE categories, corticosteroids were the most common type of systemic IMM. Some patients with GI and hepatic sTRAEs were also treated with immunosuppressive agents, including infliximab and mycophenolic acid, in addition to systemic corticosteroids (Table 2). Overall, across sTRAE categories, the resolution rates after concomitant treatment with IMMs ranged from 45% to 100% (Table 2). The median time to sTRAE resolution in patients treated with concomitant IMMs ranged from 2 to 10.6 weeks. The median time to resolution was not reached for endocrine and renal sTRAEs in patients treated with IMMs (Table 2).

In all, 29 of 119 (24%) patients had sTRAEs that led to dose delay (supplemental online Table 2). Dose delays most commonly occurred in patients with endocrine sTRAEs (10%) (supplemental online Table 2). Nivolumab plus low‐dose ipilimumab therapy was resumed in 25 patients after dose delay with 4 patients discontinuing therapy (supplemental online Table 3). All patients who had dose delay because of endocrine (n = 12) or skin (n = 2) sTRAEs resumed therapy (supplemental online Tables 2 and 3). Overall, sTRAEs were noted in 14 patients after resuming therapy, most of which were grade 1 or 2. The most common sTRAEs after resuming therapy were in the hepatic (6 patients) and endocrine (5 patients) organ categories (supplemental online Table 3).

IMAEs of special interest are summarized in Figure 2. Hypothyroidism/thyroiditis (15%) and rash (14%) were the most frequently reported IMAEs. Most IMAEs occurred early (i.e., within 12 weeks of therapy), with the median time to onset of IMAEs ranging from 3.7 to 16.3 weeks (Fig. 2). Overall, IMAEs resolved in the majority of patients (>80%) after treatment with IMMs with the median time to resolution of the IMAEs ranging from 0.1 to 10.0 weeks (Fig. 2).

Efficacy

Sixteen of 119 patients (13%) whose main reason for discontinuing treatment was a study drug‐related AE had a high ORR (63%) and DCR (81% for ≥12 weeks), with median DOR not reached [18]. The 12‐month PFS and OS rates for patients who discontinued because of TRAEs were consistent with the survival rates in the overall patient population (PFS, 76% vs. 71% and OS, 88% vs. 85%, respectively) [18].

Efficacy was maintained in patients with sTRAEs, with an ORR of 57%, which was comparable to patients without sTRAEs (52%; Table 3). Both groups included patients with CR (5% vs. 2%, respectively). The DCR was numerically higher in patients with sTRAEs compared with those without sTRAEs (90% vs. 67%, respectively; Table 3). The 12‐month PFS rates (77% vs. 63%) and OS rates (93% vs. 75%) were also numerically higher in patients with sTRAEs compared with patients who did not have sTRAEs, respectively. Kaplan‐Meier plots of PFS and OS suggested that patients in both groups had comparable survival rates across all sTRAE grades (Fig. 3A, 3B; supplemental online Fig. 1A, 1B). Patients with sTRAEs who were and were not treated with IMMs had comparable ORR and DCR (ORR, 52% vs. 57% and DCR, 84% vs. 75%, respectively). The 12‐month PFS and OS rates were also comparable between patients with sTRAEs who were and were not treated with IMMs (PFS, 70% vs. 72% and OS, 87% vs. 82%, respectively).

Discussion

In CheckMate 142, patients with previously treated MSI‐H/dMMR mCRC who received nivolumab plus low‐dose ipilimumab Q3W for four doses followed by nivolumab Q2W had high response rates, encouraging PFS and OS, and a manageable safety profile. Grade 3–4 AEs occurred in one‐third of patients, and rates of discontinuation because of any grade TRAEs were low. In the current analysis, we further explored the safety profile of nivolumab plus low‐dose ipilimumab in previously treated patients with MSI‐H/dMMR mCRC. sTRAEs were managed using protocol‐specified algorithms that directed continuation, symptomatic treatment, IMM treatment, delay, or discontinuation of therapy based on sTRAE grade and category [20]. The incidence of sTRAEs in this study, especially GI sTRAEs (any grade, 23%; grade 3–4, 3%), was similar to that noted in patients with renal cell carcinoma (any grade, 28%; grade 3–4, 5%), a non‐GI tract tumor, who were treated with the same dosage of nivolumab plus low‐dose ipilimumab (nivolumab 3 mg/kg plus 1 mg/kg ipilimumab Q3W followed by nivolumab 3 mg/kg Q2W) as a first‐line therapy [21]. Together, these data suggest that sTRAEs in the GI tract may not be related to recognition of shared tumor antigens. Overall, the sTRAEs were mostly low grade and resolved in the majority of patients with the use of established management algorithms, including concomitant IMM. Endocrine sTRAEs resolved in 40% of patients. This comparatively lower resolution rate was attributed to the continuing need for hormone replacement therapy. The majority of patients who had a dose delay because of a sTRAE resumed therapy (25 of 29 patients). sTRAEs were generally grade 1 or 2 after resuming nivolumab plus low‐dose ipilimumab.

Additional analyses of IMAEs were performed to further characterize AEs of special clinical interest. IMAEs were noted in a small percentage of patients and resolved in the majority of patients after treatment with IMMs. Patients with endocrine‐related IMAEs had comparatively lower resolution rates, as IMAEs were not considered resolved in some patients because of the ongoing need for hormone replacement therapy. In patients with other solid tumors treated with nivolumab plus ipilimumab, the safety profile appeared to be associated with the ipilimumab dose, with lower ipilimumab doses leading to reduced frequency of grade 3–4 adverse events [22, 23]. In patients with MSI‐H/dMMR mCRC from CheckMate 142, indirect comparisons suggested that nivolumab plus low‐dose ipilimumab treatment had enhanced efficacy relative to nivolumab monotherapy (ORR, 55% vs. 31%; 12‐month OS rate, 85% vs. 73%, respectively) and a manageable safety profile (grade 3–4 TRAEs, 32% vs. 20%; discontinuation because of any grade TRAEs, 13% vs. 7%, respectively) [10, 18]. Similarly, considering caveats of cross‐trial comparisons, nivolumab plus low‐dose ipilimumab demonstrated numerically higher response and survival rates relative to pembrolizumab monotherapy (ORR, 55% vs. 32%; 12‐month OS rate, 85% vs. 76%, respectively), with a manageable safety profile (grade 3–4 TRAEs, 32% vs. 11%, respectively), in previously treated patients with MSI‐H/dMMR mCRC [24].

Limited studies have evaluated the antitumor efficacy of immune checkpoint inhibitors in patients after the appearance of immune‐related AEs. We previously demonstrated that patients who discontinued treatment because of a study drug‐related AE had an ORR and DCR that were comparable to rates in patients continuing treatment [18]. In the current analysis, patients who discontinued treatment because of any sTRAE had survival rates that were comparable to the overall population. Some preclinical and clinical evidence suggests that concomitant treatment with corticosteroids to manage immune‐related AEs may compromise the antitumor response [25–27]. In this analysis, similar efficacy was achieved in patients with and without sTRAEs, as ORRs were comparable in both groups. Considering the caveats of small patient number and lack of statistical significance, a numerically higher CR rate in patients with sTRAEs compared with those without sTRAEs (5% vs. 2%) was notable. Furthermore, comparable efficacy was observed between patients with sTRAEs irrespective of concomitant IMM treatment. This suggests that the occurrence of sTRAEs and their management, including IMM therapy in some patients, did not compromise the response to nivolumab plus low‐dose ipilimumab; however, these results need to be confirmed in larger studies. Moreover, patients with sTRAEs had numerically higher DCR and 12‐month PFS and OS rates compared with patients without sTRAEs. This analysis is limited by its retrospective nature and the absence of a standard‐of‐care comparator arm that precludes direct comparison of nivolumab plus low‐dose ipilimumab therapy with other immune checkpoint inhibitor treatments. In addition, because of the small sample size of patients with sTRAEs, it is not feasible to assess whether these sTRAEs were related to specific efficacy outcomes. Pooling sTRAE categories from patients with varying underlying biology may have contributed to the comparable efficacy observed in patients both with and without sTRAEs.

Conclusion

Patients with MSI‐H/dMMR mCRC have poorer outcomes with chemotherapy than those with microsatellite stable/mismatch repair‐proficient mCRC [6–8]. Nivolumab plus low‐dose ipilimumab demonstrated durable responses, high DCR, and high survival rates in previously treated patients with MSI‐H/dMMR mCRC [18]. In this safety analysis of previously treated patients with MSI‐H/dMMR mCRC in CheckMate 142, nivolumab plus low‐dose ipilimumab had a manageable safety profile. The majority of sTRAEs and IMAEs resolved and were manageable using the recommended evidence‐based treatment algorithms for early intervention and treatment. Patients with and without sTRAEs had comparable ORR and survival rates. Similarly, patients with sTRAEs had comparable ORR and survival rates regardless of treatment with concomitant IMM. The benefit‐risk profile of nivolumab plus low‐dose ipilimumab provides a promising treatment option for patients with previously treated MSI‐H/dMMR mCRC.

Acknowledgments

We thank the patients and their families for making the study possible; the clinical study teams; the investigators, Dako, an Agilent Technologies, Inc. company, for collaborative development of the PD‐L1 IHC 28‐8 pharmDx assay, Bristol‐Myers Squibb (Princeton, NJ) and ONO Pharmaceutical Company Ltd. (Osaka, Japan). This study was funded by Bristol‐Myers Squibb. Medical writing and editorial support in the preparation of this paper was provided by Tanmayi Mankame, Ph.D., and Christine Craig, M.S., of Parexel, funded by Bristol‐Myers Squibb.

Bristol‐Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.

Author Contributions

Conception/design: Michael A. Morse, Michael J. Overman, Leighanne Hartman, Taline Khoukaz, Edith Brutcher, Heinz‐Josef Lenz, Ajlan Atasoy, Tong Shangguan, Huanyu Zhao, Bassel El‐Rayes

Provision of study material or patients: Michael A. Morse, Michael J. Overman, Leighanne Hartman, Taline Khoukaz, Edith Brutcher, Heinz‐Josef Lenz, Ajlan Atasoy, Tong Shangguan, Huanyu Zhao, Bassel El‐Rayes

Collection and/or assembly of data: Michael A. Morse, Michael J. Overman, Leighanne Hartman, Taline Khoukaz, Edith Brutcher, Heinz‐Josef Lenz, Bassel El‐Rayes

Data interpretation: Michael A. Morse, Michael J. Overman, Leighanne Hartman, Taline Khoukaz, Edith Brutcher, Heinz‐Josef Lenz, Ajlan Atasoy, Tong Shangguan, Huanyu Zhao, Bassel El‐Rayes

Data Analysis: Ajlan Atasoy, Tong Shangguan, Huanyu Zhao

Manuscript writing: Michael A. Morse, Michael J. Overman, Leighanne Hartman, Taline Khoukaz, Edith Brutcher, Heinz‐Josef Lenz, Ajlan Atasoy, Tong Shangguan, Huanyu Zhao, Bassel El‐Rayes

Final approval of manuscript: Michael A. Morse, Michael J. Overman, Leighanne Hartman, Taline Khoukaz, Edith Brutcher, Heinz‐Josef Lenz, Ajlan Atasoy, Tong Shangguan, Huanyu Zhao, Bassel El‐Rayes

Disclosures

Michael Morse: Celgene, Genentech/Roche, Lexicon, Novartis, Taiho Pharmaceutical (other‐speakers bureau), Astellas Pharma, Bayer, Boehringer Ingelheim, EMD Serono, Etubics, Genentech/Roche, Ipsen, Lexicon, Merrimack, Novartis, Onyx, Regeneron, Sanofi, Taiho Pharmaceutical (H), Advanced Accelerator Applications, AlphaVax, Bristol‐Myers Squibb, Eisai, Lexicon, MedImmune, Merck, Onyx, Precision Biologics, AstraZeneca AB, Halozyme, Inc., H3 Biomedicine, Inc. (RF), PhytoChem (OI); Heinz‐Josef Lenz: Bristol‐Myers Squibb (SAB, other‐clinical trials support), Bayer, Genentech, Merck KG (SAB), Bayer, Genentech, Merck KG (other‐lectures); Ajlan Atasoy: Bristol‐Myers Squibb (E); Tong Shangguan: Bristol‐Myers Squibb (E); Huanyu Zhao: Bristol‐Myers Squibb (E); Bassel El‐Reyes: Bristol‐Myers Squibb, Merck, Pfizer, BBI, Bayer, Roche, Synta (RF), Ipsen, Eli Lilly & Co, Bristol‐Myers Squibb, Roche (SAB), Lexicon (H). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

References

Author notes