Modified FOLFOX6 plus bevacizumab with and without nivolumab for first-line treatment of metastatic colorectal cancer: phase 2 results from the CheckMate 9X8 randomized clinical trial

Abstract

Background

Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8).

Methods

CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed.

Results

From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3–4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified.

Conclusions

The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted.

Trial registration number

NCT03414983.

Correspondence to Dr Heinz-Josef Lenz; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent are standard first-line therapeutic options for metastatic colorectal cancer (mCRC). Immunotherapeutic approaches have demonstrated clinical efficacy in several tumor types, including microsatellite instability-high/mismatch repair-deficient mCRC, and often result in deep and durable responses. The addition of nivolumab to standard-of-care (SOC) chemotherapy-based regimens may enhance efficacy in the first-line setting for mCRC as has been shown in clinical studies of other tumor types.

WHAT THIS STUDY ADDS

• In CheckMate 9X8, the primary endpoint of progression-free survival by blinded independent central review was not met with first-line nivolumab plus SOC versus SOC alone in patients with mCRC, although nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses versus SOC, along with acceptable safety.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• These results warrant further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC in the first-line setting.

Introduction

Colorectal cancer (CRC) is the third most common malignancy, and the second leading cause of cancer-related death worldwide, with almost 1 million deaths in 2020.¹ In the USA, the 5-year relative survival rate for patients with metastatic CRC (mCRC) remains poor (~14%).² Standard first-line therapeutic options for mCRC include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent such as a vascular endothelial growth factor or epidermal growth factor receptor inhibitor.³ In patients with mCRC, first-line chemotherapy plus bevacizumab (BEV) has demonstrated a median progression-free survival (PFS) of 9.4–10.6 months by investigator assessment, a median overall survival (OS) of 21.3–29.0 months,^{4 5} and an objective response rate (ORR) of 38% by blinded independent central review (BICR).⁴

Immunotherapeutic approaches have demonstrated clinical efficacy in several tumor types, including microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) mCRC, and often result in deep and durable responses.^6–10 In patients with MSI-H/dMMR mCRC, the programmed death-1 (PD-1) inhibitor nivolumab provided durable responses as monotherapy¹⁰ or in combination with the cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab.^{6 9} National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) include nivolumab or nivolumab plus ipilimumab as an initial therapy option for patients with MSI-H/dMMR mCRC.^{11 12}

The addition of nivolumab to standard-of-care (SOC) chemotherapy-based regimens may enhance efficacy in the first-line setting for mCRC as has been shown in clinical studies of other tumor types.^13–15 Here, we report the results of nivolumab plus SOC (5-fluorouracil/leucovorin/oxaliplatin plus BEV (mFOLFOX6/BEV)) versus SOC alone as a first-line therapy in mCRC from the CheckMate 9X8 trial. Additionally, preplanned exploratory analyses were performed and select biomarkers were evaluated to identify subgroups of patients with mCRC that may experience benefit with nivolumab plus SOC in the first-line setting.

Methods

Trial design and patients

CheckMate 9X8 is a multicenter, randomized, open-label, phase 2/3 trial. Enrollment occurred at 45 sites in four countries (online supplemental material). Eligible patients were at least 18 years of age, with histologically confirmed mCRC not amenable to curative resection and no prior chemotherapy for metastatic disease. Other key inclusion criteria were measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and an Eastern Cooperative Oncology Group performance status of 0 or 1.^{16 17} Patients with prior treatment with an anti-PD-1, anti-programmed death ligand 1 (PD-L1)/2, anti-CTLA-4, or other antibody or drug targeting T-cell co-stimulation or checkpoint pathways were excluded. Patients were randomized 2:1 to receive nivolumab plus SOC or SOC alone. Randomization was done using interactive response technology (block size: 6); stratification factors were tumor sidedness (left, right, transverse, or unknown) and prior oxaliplatin-based adjuvant chemotherapy (yes or no).

The trial protocol is available in the online supplemental material.

Procedures

Patients received nivolumab (240 mg as a 30 min infusion) every 2 weeks on day 1 of each treatment cycle, for a maximum of 24 months. Treatment regimens for mFOLFOX6/BEV were: oxaliplatin, 85 mg/m²; leucovorin, 400 mg/m² or 350 mg/m² per local standards; fluorouracil, bolus 400 mg/m², followed by fluorouracil, 1200 mg/m² continuous infusion on day 1 and day 2, or 2400 mg/m² continuous infusion over 46–48 hours from day 1 through day 2 per local standards; BEV was administered at 5 mg/kg. All treatments were administered intravenously every 2 weeks, and continued until disease progression, unacceptable toxicity, consent withdrawal, or trial end. Dose modifications (reductions or escalations) for nivolumab were not permitted; nivolumab doses may have been interrupted, delayed, or discontinued, depending on tolerability. Dose modifications were allowed for mFOLFOX6 components and BEV per local or institutional standards.

Outcomes and assessments

The primary endpoint was PFS (time from randomization to the date of the first documented progression or death due to any cause, whichever occurred first) by BICR per RECIST V.1.1. Secondary endpoints were PFS by investigator assessment; ORR, disease control rate (DCR), duration of response (DOR), time to response, all by BICR and investigator assessments; OS; and safety. Exploratory endpoints included biomarker analyses.

Tumors were assessed using CT or MRI per RECIST V.1.1 within 28 days prior to the first dose; post-baseline measurements were performed at week 12 after randomization, and then every 8 weeks thereafter until confirmed progression, withdrawal of consent, or trial end. Complete response (CR) and partial response (PR) were confirmed by a second scan at least 4 weeks after initial response. Safety assessments were evaluated per the National Cancer Institute Common Terminology Criteria for Adverse Events V.4.0 continuously at each study visit throughout treatment and for at least 100 days after treatment discontinuation.¹⁸ The causal relationship to the study drug was determined by the investigator. See online supplemental methods for additional details.

Statistical methods

ORR was summarized by binomial response rates, and the corresponding two-sided 95% exact CIs were calculated by the Clopper-Pearson method. Kaplan-Meier product-limit method was used for the estimation of medians for DOR, PFS, and OS; corresponding 95% CIs were calculated using log–log transformation. Safety was analyzed in all patients who received at least one dose of study treatment. Patient characteristics and safety data were summarized using descriptive statistics. Statistical analyses were performed using SAS software V.9.2 (SAS Institute, Cary, North Carolina, USA).

A phase 2 interim analysis would guide phase 3 expansion: a strong efficacy signal among all randomized patients with no substantial differential effects by subgroups, and an overall favorable benefit/risk with nivolumab plus SOC versus SOC would allow for a potential phase 3 expansion. See online supplemental methods for additional details.

Results

Baseline characteristics and patient disposition

From February 2018 through April 2019, 310 patients were enrolled, of which 195 were randomized 2:1 to nivolumab plus SOC (n=127) and SOC (n=68). At data cut-off (February 1, 2021), 185 patients (nivolumab plus SOC, n=123; SOC, n=62) received at least one dose as assigned (figure 1). The minimum follow-up (time from randomization of the last patient to clinical data cut-off) was 21.5 months. Median (range) follow-up (time from randomization to last known date alive or death) was 23.7 (0–33.2) months in the nivolumab plus SOC arm and 23.2 (0–32.3) months in the SOC arm. The median (range) age of patients was 58 (24–85) years and 56 (24–78) years, and 55% and 72% were men in the nivolumab plus SOC and SOC arms, respectively (table 1). At data cut-off, 119 (97%) patients in the nivolumab plus SOC arm and 60 (97%) patients in the SOC arm had discontinued treatment; the most common reason for treatment discontinuation in both arms was disease progression (nivolumab plus SOC, n=72 (59%); SOC, n=27 (44%; figure 1). Among patients who discontinued treatment, 76 (60%) patients in the nivolumab plus SOC arm and 39 (57%) patients in the SOC arm received subsequent therapy (online supplemental table 1).

Table 1

Baseline patient demographics and clinical characteristics

All randomized	NIVO+SOC (n=127)	SOC (n=68)
Median age (range), years	58 (24–85)	56 (24–78)
<65 years	89 (70)	47 (69)
Male	70 (55)	49 (72)
Race
White	96 (76)	57 (84)
Asian	15 (12)	5 (7)
Black	8 (6)	2 (3)
Other/not reported	8 (6)	4 (6)
ECOG PS
0	76 (60)	41 (60)
1	51 (40)	27 (40)
Metastatic disease at study entry*	126 (99)	68 (100)
Initial metastatic disease location†
Liver	86 (68)	44 (65)
Lung	49 (39)	22 (32)
Lymph node	30 (24)	13 (19)
Tumor sidedness per IRT‡
Left	76 (60)	39 (57)
Right	31 (24)	16 (24)
Transverse	8 (6)	4 (6)
Prior oxaliplatin therapy per IRT	7 (6)	4 (6)
Microsatellite instability§
MSS/pMMR	121 (95)	61 (90)
MSI-H/dMMR	6 (5)	7 (10)
KRAS mutation status¶
Wild type	72 (57)	31 (46)
G12D/V/C	28 (22)	17 (25)
Other mutation	27 (21)	19 (28)
Tumor cell PD-L1 expression**
≥1%	15 (12)	6 (9)
<1%	111 (87)	62 (91)
PD-L1 CPS††‡‡
≥1	82 (67)	38 (61)
<1	40 (33)	24 (39)
CMS category††§§¶¶
CMS1	14 (11)	6 (10)
CMS2	25 (20)	11 (18)
CMS3	17 (14)	5 (8)
CMS4	26 (21)	17 (27)
TMB††¶¶***†††
TMB-bottom (≤54 mutations/exome)	27 (22)	11 (18)
TMB-middle (>54 to ≤74 mutations/exome)	28 (23)	9 (15)
TMB-top (>74 mutations/exome)	24 (20)	13 (21)

Data are No. (%) unless otherwise noted.

*Disease stage was not reported in one patient in the NIVO+SOC arm.

†A patient may have more than one metastatic disease location.

‡Tumor sidedness was unknown in 21 patients (NIVO+SOC, n=12; SOC, n=9).

§Six MSI-L patients (NIVO+SOC, n=1; SOC, n=5) are included in the MSS/pMMR category; two patients with dMMR per IHC (one from each arm) are included in the MSS/pMMR category based on their PCR result of MSS.

¶KRAS mutation status was not reported in one patient in the SOC arm.

**One patient in the NIVO+SOC arm had PD-L1 levels that were not quantifiable.

††All treated patients (NIVO+SOC, n=123; SOC, n=62). Percentages are calculated based on the number of all treated patients.

‡‡PD-L1 CPS was not evaluable in one patient in the NIVO+SOC arm.

§§Sixty-four patients (NIVO+SOC, n=41; SOC, n=23) had CMS status that were unknown, not available, or not reported.

¶¶Evaluated only in patients with sufficient tumor samples for sequencing analyses.

***Baseline TMB levels were generally low in this study; therefore, a lower TMB threshold was used to classify patients into subgroups instead of the threshold of 200 mutations/exome used in other tumor types.

†††TMB status was not evaluable in 73 patients (NIVO+SOC: n=44; SOC: n=29).

CMS, consensus molecular subtype; CPS, combined positive score; dMMR, mismatch repair-deficient; ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; IRT, interactive response technology; KRAS, Kirsten rat sarcoma viral oncogene homolog; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; NIVO, nivolumab; PD-L1, programmed death ligand 1; pMMR, mismatch repair-proficient; SOC, standard of care; TMB, tumor mutational burden.

Figure 1. Consolidated Standards of Reporting Trials diagram. a Other reasons included poor/non-compliance (n=1), and additional reasons (n=19). b Median (range) follow-up was 23.7 (0-33.2) months in the nivolumab plus SOC arm and 23.2 (0-32.3) months in the SOC arm. c Other reasons included completion of treatment per protocol (n=8), withdrawal of consent (n=4), poor/non-compliance (n=2), and additional reasons (n=4). d Other reasons included withdrawal of consent (n=3), death (n=2), lost to follow-up (n=1), and additional reasons (n=2). AE, adverse event; NIVO, nivolumab; OS, overall survival; PFS, progression-free survival; SOC, standard of care.

The median (range) duration of therapy was 9.9 (0.1–31.8+) months with nivolumab plus SOC versus 7.7 (0.1–26.7+) months with SOC; 77% and 55% of patients had a duration of therapy ≥6 months in the nivolumab plus SOC and SOC arms, respectively. In the nivolumab plus SOC arm, the median number of nivolumab doses received was 17 (range, 1–52), and 54% of patients received ≥90% of the planned relative dose intensity of nivolumab. In the SOC arm, relative dose intensities ≥90% of mFOLFOX6 components and BEV were higher (nivolumab plus SOC arm, 28–41%; SOC, 47–65%), and the proportion of patients experiencing ≥1 dose reduction in the mFOLFOX6 components was lower compared with the nivolumab plus SOC arm; in both arms, the majority of patients experienced ≥1 dose delay (nivolumab plus SOC, 72–83% and SOC, 61–71%, for the regimen components; online supplemental table 2).

Efficacy

Median PFS by BICR was 11.9 months (95% CI, 8.9 to 15.7) in the nivolumab plus SOC arm and 11.9 months (95% CI, 10.1 to 12.2) in the SOC arm (HR, 0.81 95% CI, 0.53 to 1.23); p=0.30); the primary endpoint of PFS by BICR was not met (figure 2). PFS curves overlapped before separating at approximately 12 months, after which numerically higher PFS rates were observed with nivolumab plus SOC versus SOC (15-month rate, 45% vs 22%; 18-month rate, 28% vs 9%). PFS by investigator assessment was comparable to PFS by BICR (online supplemental figure 1); concordance between these two assessments was 85% in the nivolumab plus SOC arm, and 88% in the SOC arm (online supplemental table 3). PFS by BICR showed a numerical trend favoring nivolumab plus SOC across multiple subgroups (HR<1) (figure 3).

Figure 2. Kaplan-Meier estimates of progression-free survival by BICR in all randomized patients. a Minimum follow-up of 21.5 months. BICR, blinded independent central review; NIVO, nivolumab; PFS, progression-free survival; SOC, standard of care.

Figure 3. Subgroup analysis of progression-free survival by BICR. a 13 patients (NIVO+SOC: n=10; SOC: n=3) were >=75 years. b Tumor sidedness was unknown in 21 patients (NIVO+SOC: n=12; SOC: n=9). c HR is not computed for categories with less than 10 patients per treatment group. d Liver metastases status was not evaluable in 10 patients (NIVO+SOC: n=5; SOC: n=5). e Six MSI-L-patients (NIVO+SOC, n=1; SOC: n=5) included in the MSS/pMMR category; two patients with dMMR per IHC (one from each arm) are included in the MSS/pMMR category based on their PCR result of MSS. f KRAS mutation status was not reported in one patient in the SOC arm. g PD-L1 expression was not quantifiable in one patient in the NIVO+SOC arm. h All treated patients. i PD-L1 CPS was not evaluable in one patient in the NIVO+SOC arm. j CMS category was unknown, not available, or not reported in 64 patients (NIVO+SOC, n=41; SOC, n=23). k Evaluated only in patients with sufficient tumor samples for sequencing analyses. l Baseline TMB levels were generally low in this study; therefore, a lower TMB threshold was used to classify patients into subgroups instead of the threshold of 200 mutations/exome used in other tumor types. m TMB status was not evaluable in 73 patients (NIVO+SOC: n=44; SOC: n=29). BICR, blinded independent central review; CMS, consensus molecular subtype; CPS, combined positive score; dMMR, mismatch repair deficient; ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; IRT, interactive response technology; KRAS, Kirsten rat sarcoma viral oncogene homolog; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; NA, not applicable; NIVO, nivolumab; PD-L1, programmed death ligand 1; pMMR, mismatch repair-proficient; SOC, standard of care; TMB, tumor mutational burden.

ORR by BICR was 60% (95% CI, 51% to 68%) in the nivolumab plus SOC arm and 46% (95% CI, 33% to 58%) in the SOC arm; the DCR was 91% (95% CI, 84% to 95%) and 84% (95% CI, 73% to 92%), respectively (table 2). Median DOR was 12.9 months (95% CI, 9.0 to 13.1) in the nivolumab plus SOC arm versus 9.3 months (95% CI, 7.5 to 11.3) in the SOC arm (≥12-month rate, 52% vs 31%; ≥18-month rate, 29% vs 0%; table 2). Antitumor activity by investigator assessment was generally similar to results by BICR (online supplemental table 4).

Table 2

Antitumor activity by BICR

All randomized	NIVO+SOC (n=127)	SOC (n=68)
ORR,* No. (%) (95% CI)	76 (60) (51 to 68)	31 (46) (33.5 to 58)
Best overall response, No. (%)
Complete response	6 (5)	1 (1)
Partial response	70 (55)	30 (44)
Stable disease	39 (31)	26 (38)
Progressive disease	3 (2)	0
Unable to determine	9 (7)	11 (16)
DCR,† No. (%) (95% CI)	115 (91) (84 to 95)	57 (84) (73 to 92)
Median TTR (range),‡ mo	2.8 (1.5 to 12.2)	2.8 (1.8 to 8.3)
Median DOR (95% CI),‡ mo	12.9 (9.0 to 13.1)	9.3 (7.5 to 11.3)
≥12-month rate (95% CI), %	52 (39 to 64)	31 (14 to 50)
≥18-month rate (95% CI), %	29 (17 to 42)	0 (NE)

*Patients with the best overall response of CR+PR divided by the number of randomized patients.

†Patients with the best overall response of CR+PR+SD divided by the number of randomized patients.

‡Evaluated in patients who had an objective response.

BICR, blinded independent central review; CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not evaluable; NIVO, nivolumab; ORR, objective response rate; PR, partial response; SD, stable disease; SOC, standard of care; TTR, time to response.

Median OS was 29.2 months (95% CI, 24.0 to not evaluable (NE)) in the nivolumab plus SOC arm and was not reached (95% CI, 24.4 months to NE) in the SOC arm (HR, 1.03 (95% CI, 0.64 to 1.66); figure 4); 15-month and 18-month OS rates were comparable between the nivolumab plus SOC and SOC arms (15-month rate, 80% (95% CI, 71% to 86%) vs 78% (95% CI, 65% to 86%); 18-month rate, 75% (95% CI, 66% to 81%) vs 76% (95% CI, 63% to 85%)).

Figure 4. Kaplan-Meier estimates of overall survival in all randomized patients. a Minimum follow-up of 21.5 months. NIVO, nivolumab; NE, not evaluable; OS, overall survival; SOC, standard of care.

Safety

Any-grade treatment-related adverse events (TRAEs) were reported in 98% of patients with nivolumab plus SOC and 97% of patients with SOC; rates of grade 3–4 TRAEs were higher with nivolumab plus SOC (nivolumab plus SOC, 75%; SOC, 48%); there were no grade 5 events with nivolumab plus SOC and one grade 5 event of cardiac arrest with SOC (online supplemental table 5). The most common any-grade TRAEs reported in both treatment arms included fatigue (46% vs 47%) and nausea (46% vs 37%). A higher incidence of any-grade serious TRAEs (28% vs 18%), TRAEs leading to discontinuation (57% vs 35%), and TRAEs leading to dose delays (72% vs 48%) were noted in the nivolumab plus SOC versus SOC arm, respectively (online supplemental table 5). Four treatment-related deaths were reported: two in the nivolumab plus SOC arm (one event each of pneumonitis (grade 4) and fulminant type myocarditis (grade 4)) and two in the SOC arm (one event each of bowel perforation (grade 4) and cardiac arrest (grade 5)).

Any-grade TRAEs with potential immunologic etiology occurred in 42% (gastrointestinal), 27% (skin), 22% (endocrine), 18% (hepatic), 4% (renal), and 4% (pulmonary) of patients in the nivolumab plus SOC arm (online supplemental table 6); most were grade 1–2, and no grade 5 events were reported. In the nivolumab plus SOC arm, TRAEs of potential immunologic etiology began within a median of 4.3–29.0 weeks depending on organ category; any-grade TRAEs resolved in the majority of patients with a median of 2.0–13.9 weeks with the exception of skin and endocrine events (online supplemental table 6).

Biomarker analyses

In exploratory subgroup analyses, PFS favored nivolumab plus SOC versus SOC in patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) G12D/V/C mutations at baseline (median PFS, 12.0 months (95% CI, 8.2 to 19.4) vs 10.3 months (95% CI, 6.5 to 12.2)), but not in those with wild-type KRAS (figure 3; online supplemental figure 2). PFS trends were maintained when MSI-H/dMMR patients (n=13) were excluded from the analysis, with median PFS comparable between all randomized and microsatellite stable/mismatch repair-proficient (MSS/pMMR) patients (figure 2 and figure 5A); PFS benefit in the MSI-H/dMMR population could not be characterized fully due to the low number of patients.

Figure 5. Kaplan-Meier estimates of progression-free survival by BICR in patient subgroups. Progression-free survival in all randomized MSS/pMMR patients (A), all treated patients with CMS status at baseline (B), all treated MSS/pMMR patients with CMS status at baseline (C), all treated MSS/pMMR patients by CMS subsets at baseline (D), and all treated MSS/pMMR patients with PD-L1 CPS>=1 at baseline (E). a Six MSI-L patients (nivolumab plus SOC, n=1; SOC, n=5) are included in the MSS/pMMR category; two patients with dMMR per IHC (one from each arm) are included in the MSS/pMMR category based on their PCR result of MSS. b 13 patients (nivolumab plus SOC, n=6; SOC, n=7) were MSI-H and were excluded from this analysis. c CMS status was evaluated only in patients with sufficient tumor samples for sequencing analyses. d CMS classifier random forest method was used for CMS classification. e Patients with unknown CMS status were excluded from the analyses. BICR, blinded independent central review; CMS, consensus molecular subtype; CPS, combined positive score; IHC, immunohistochemistry; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; NE, not evaluable; PD-L1, programmed death ligand 1; PFS, progression-free survival; pMMR, mismatch repair-proficient; SOC, standard of care.

Among patients who had sufficient quantity and quality of tumor tissue, numerically longer PFS was observed with nivolumab plus SOC versus SOC in the consensus molecular subtype 3 (CMS3) subgroup (median PFS, 16.1 months (95% CI, 8.1 to NE) vs 8.7 months (95% CI, 6.9 to NE) in all treated patients (figure 5B) and in those with baseline MSS/pMMR (figure 5C)). After 12 months, PFS also favored nivolumab plus SOC in MSS/pMMR patients with CMS1 and CMS3 at baseline (figure 5D).

Baseline tumor mutational burden (TMB) levels were low in this study (median, 64.5 mutations/exome) and did not show an association with PFS or response to therapy in either treatment arm (online supplemental figure 3A and B). Additionally, no associations were observed between baseline PD-L1 expression (combined positive score (CPS)≥1) and PFS in MSS/pMMR patients (figure 5E) and all treated patients (online supplemental figure 3C). Few patients had baseline tumor cell PD-L1 expression ≥1% (nivolumab plus SOC, n=15; SOC, n=6), and therefore, median PFS was not calculated in this subgroup.

Discussion

Phase 2 results from the CheckMate 9X8 trial did not demonstrate a statistically significant improvement in median PFS with nivolumab plus SOC versus SOC in the first-line treatment of patients with mCRC. The PFS curves overlapped before separating at approximately 12 months; nivolumab plus SOC showed numerically higher PFS rates after 12 months compared with SOC. PFS subgroup analyses showed a numerical trend favoring nivolumab plus SOC across multiple subgroups (HR<1). HRs were less than 1 in most evaluated subgroups, which showed numerical improvements; however, as patient numbers in some of these categories were low, wide 95% CIs were expected. Nivolumab plus SOC showed higher ORR and CR rates, and more durable responses compared with SOC. Median OS was 29.2 months in the nivolumab plus SOC arm and was not reached in the SOC arm. The minimum follow-up for the secondary endpoint of OS was 21.5 months; however, a longer follow-up may be required for this analysis.

The median duration of therapy was longer with nivolumab plus SOC versus SOC (9.9 months vs 7.7 months). However, relative dose intensities of mFOLFOX6 components and BEV were lower with nivolumab plus SOC versus SOC. The proportion of patients experiencing at least one dose delay (mFOLFOX6 components and BEV) or at least one dose reduction (mFOLFOX6 components) was lower with SOC versus nivolumab plus SOC.

The safety profile of nivolumab plus SOC was consistent with the known safety profiles of the chemotherapy and immunotherapy components; no new safety signals were identified with nivolumab plus SOC.^{5 10 19 20} The frequency of grade 3–4 TRAEs, serious TRAEs, and TRAEs leading to discontinuation or dose delays was generally higher in the nivolumab plus SOC arm compared with the SOC arm. This was consistent with similar studies comparing nivolumab plus chemotherapy to chemotherapy alone.^{13 15} The majority of TRAEs with potential immunologic etiology were low grade; grade 3–4 events occurred in 5% or less of patients across most organ categories with nivolumab plus SOC (with the exception of gastrointestinal events (13%)) and were manageable using protocol-specified management guidelines. The incidence of treatment-related deaths was similar between the two treatment arms.

Additionally, this trial explored biomarkers that may segment mCRC by the expected response to therapy. PFS trends were comparable between all randomized and MSS/pMMR patients, suggesting that PFS benefit after 12 months was not driven by the small number of patients with baseline MSI-H/dMMR. In the first-line setting, tumors with high TMB have shown higher response rates and longer PFS than those with low TMB.^{21 22} However, baseline TMB levels were low in this study, which may explain the lack of an association of TMB with PFS. CMS is an independent prognostic marker for patients with mCRC.^{23 24} In exploratory subgroup analyses, PFS, after 12 months, favored nivolumab plus SOC in MSS/pMMR patients with CMS1 and CMS3 at baseline; the PFS curves for nivolumab plus SOC versus SOC in this subgroup overlapped before separating at approximately 12 months, suggesting that these patients may benefit with the addition of nivolumab to SOC. CSM3 tumors are characterized by their enrichment for multiple metabolic signatures, including an increased frequency of KRAS mutations.²⁵ However, as CMS3 and KRAS status do not completely overlap, it is likely that both of these biomarkers may be independently contributing to the observed responses. The clinical relevance of CMS in mCRC, including CMS3, has been previously investigated in established first-line SOC across several clinical trials; however, evidence supporting associations between specific consensus molecular subtypes and the clinical efficacy of immunotherapy in mCRC is currently lacking.²⁶ The limited number of patients with CMS3 tumors in this study and the potential confounding effect of KRAS mutations limit the interpretation of our results in the CMS subgroup. The predictive value of baseline PD-L1 levels in mCRC remains unclear^{6 9 10}; consistent with this, baseline tumor cell PD-L1 expression or PD-L1 CPS did not impact PFS in our analyses.

Combinations of immunotherapy with chemotherapies have been explored in the first-line setting for mCRC.^27–29 In a phase 1b single-arm clinical trial of first-line pembrolizumab plus mFOLFOX6 in mCRC, the median PFS was 8.8 months, and the median OS was not reached.²⁹ Benefit with first-line atezolizumab plus FOLFOXIRI/BEV versus FOLFOXIRI/BEV alone was observed in PFS (median PFS, 13.1 months vs 11.5 months; HR, 0.69 (80% CI, 0.56 to 0.85); p=0.012), but not in ORR (59% vs 64%, p=0.21).²⁷ The addition of atezolizumab to fluoropyrimidine/BEV did not improve efficacy outcomes in the first-line maintenance setting for BRAF wild-type mCRC compared with fluoropyrimidine/BEV alone (median PFS, 7.13 months vs 7.36 months; HR, 0.95 (95% CI, 0.77 to 1.18); p=0.666).²⁸ However, it is important to note that direct cross-study comparisons may not be appropriate due to differences in study design and patient populations.

At the predefined interim analysis, the ORR in the overall population and the biomarker subgroups in phase 2 did not meet the prespecified criteria to expand into phase 3. Therefore, per the trial protocol, CheckMate 9X8 continued as a phase 2 trial.

A limitation of CheckMate 9X8 was its open-label design, which may have resulted in biases in the reporting of treatment benefits and adverse events. Additionally, PFS rates beyond 12 months should be interpreted with caution due to the small number of patients. The biomarker analyses were exploratory, and only included the subset of patients who had sufficient quantity and quality of tumor tissue, limiting the number of patients in those subgroups. Due to the low patient numbers in some of these subgroups, these data should also be interpreted with caution; further studies to characterize these biomarkers are ongoing.

In conclusion, the CheckMate 9X8 trial did not meet its primary endpoint of PFS by BICR, with no improvement in median PFS observed with first-line nivolumab plus SOC versus SOC in patients with mCRC. Numerically higher PFS rates after 12 months, a higher response rate, and more durable responses with nivolumab plus SOC versus SOC warrant further investigation to identify subgroups that may benefit from nivolumab plus SOC in the first-line setting.

We thank the patients and their families for making the study possible; the clinical study teams who participated in the study; Rachel Tam and Shruthi Ravimohan for the execution of the translational medicine plans; Dako (an Agilent Technologies Inc. company, Santa Clara, California, USA) for collaborative development of the PD-L1 IHC 28-8 pharmDx assay; and Bristol Myers Squibb (Princeton, New Jersey, USA) and Ono Pharmaceutical Company Ltd. (Osaka, Japan). All authors contributed to and approved the manuscript. Medical writing and editorial assistance were provided by Dhivya Ramalingam, PhD, of Parexel, funded by Bristol Myers Squibb.

Data availability statement

Data are available upon reasonable request. 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.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

This study involved human participants and multiple committees and IRBs were involved. This trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines developed by the International Council for Harmonisation and in compliance with the trial protocol. The trial protocol and amendments were approved by the institutional review board or independent ethics committee at each trial site, and all patients provided written informed consent prior to enrollment. The report was prepared according to the Consolidated Standards of Reporting Trials (CONSORT).

Footnote

Presented at Presented in part at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, San Francisco, California, and Online, January 20–22, 2022.

Contributors All authors contributed to the manuscript. Guarantor: H-JL.

Funding The study was supported by Bristol Myers Squibb.

Competing interests H-JL reports consulting or advisory roles for Bayer, Bristol Myers Squibb, GlaxoSmithKline, Merck Serono, and Roche; honoraria from Bayer, Boehringer Ingelheim, Fulgent Genetics, GlaxoSmithKline, G1 Therapeutics, Isofol Medical, Jazz Pharmaceuticals, Merck Serono, Oncocyte, and Roche; travel, accommodations, and expenses from Bayer and Merck Serono. AP reports equity in C2i Genomics; advisor/consultant roles for Eli Lilly, Pfizer, Inivata, Biofidelity, Natera, Checkmate Pharmaceuticals, FMI, Guardant, AbbVie, Bayer, and Taiho; served on the DSMC for a Roche study; and has received research funding to the institution from PureTech, PMV Pharmaceuticals, Plexxicon, Takeda, Bristol Myers Squibb, Mirati Therapeutics, Novartis, Genentech, Natera, and Daiichi Sankyo. DRS reports consulting or advisory roles for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Curio Science, EMD Serono, Evelo Therapeutics, Evidera, Exelixis, Genentech/Roche, GlaxoSmithKline, Intellisphere, Ipsen, Janssen, Jazz Pharmaceuticals, Eli Lilly, Mirati Therapeutics, Molecular Templates, Novartis, Novocure, Pfizer, Puma Biotechnology, Regeneron, Sanofi/Aventis, and Takeda; leadership roles at ASCO; travel, accommodations, and expenses from AstraZeneca, Genentech, and Novartis; and has received research funding to institution from Aeglea Biotherapeutics, Agios, Apollomics, Arcus Biosciences, Arrys Therapeutics, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Celgene, Celldex, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, EMD Serono, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Immunogen, Incyte, Ipsen, Janssen Oncology, Kronos Bio, Eli Lilly, Loxo, Macrogenics, MedImmune, Merck, Molecular Partners, Molecular Templates, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Pfizer, PTC Therapeutics, PureTech, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics Inc., Transgene, University of Texas Southwestern Medical Center–Simmons Cancer Center, and Verastem. ALC reports honoraria from Amgen; and has provided expert testimony for the Department of Justice. TY reports honoraria from Chugai Pharmaceuticals, Merck, Bayer Yakuhin, Ono Pharmaceutical Co., Ltd, Eli Lilly, and Taiho Pharmaceuticals; and research funding from Chugai Pharmaceuticals, Merck Sharp & Dohme Corporation, Daiichi Sankyo, Parexel, Ono Pharmaceutical Co., Ltd, Taiho Pharmaceuticals, Amgen, and Sanofi. EE reports honoraria from Servier, Array Biopharma, Roche, Bristol Myers Squibb, Merck Serono, and Sanofi/Aventis; honoraria from Boehringer Ingelheim, Amgen, GlaxoSmithKline, AbbVie/Genetech, Novartis, MSD, and AstraZeneca (to institution); consulting and advisory roles for Array BioPharma, Bristol Myers Squibb, Roche, Servier, Sanofi, Amgen, Merck Serono, and Bayer; research funding from Merck Serono and Amgen; and research funding (to institution) from Sanofi/Aventis, Servier, Bristol Myers Squibb, Array BioPharma, Roche, Pierre Fabre, and MedImmune; and travel and accommodations from Servier. DD reports consulting roles for Bayer, Promega, Array Biopharma, Eli Lilly, and Pfizer; and research funding from Merck, Bristol Myers Squibb, Genentech, Revolution Medicines, Millenium Pharmaceuticals, and Bayer. EC reports honoraria from Eisai and Bayer; and research funding from Bristol Myers Squibb, Merck, Novartis, Boston Biomedical, AstraZeneca, and Zymeworks. AM reports consulting or advisory roles for QED Therapeutics; honoraria from Eisai; and research funding from Taiho Pharmaceuticals. EB-B was an employee of Bristol Myers Squibb at the time of the study and reports consulting or advisory roles for Bristol Myers Squibb, Fennec Pharmaceuticals, Green3Bio, Geistlich Pharma, Oncternal Therapeutics, and Shasqi Inc; leadership roles in Catalyst Clinical Research; travel, accommodations, and expenses from Geistlich Pharma; and stock and other ownership interests in Oncternal Therapeutics and Catalyst Clinical Research. TK reports being an employee of Bristol Myers Squibb. DC, ABH, and JY report being employees of and owning stock in Bristol Myers Squibb. JT reports consulting roles for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; stocks from Oniria Therapeutics; and educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource (PER). All other authors report no conflicts of interest.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

References

¹ Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209–49. doi:10.3322/caac.21660

² Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin 2017; 67: 177–93. doi:10.3322/caac.21395

³ Grapsa D, Syrigos K, Saif MW. Bevacizumab in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for first-line and maintenance treatment of metastatic colorectal cancer. Expert Rev Anticancer Ther 2015; 15: 1267–81. doi:10.1586/14737140.2015.1102063

⁴ Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26: 2013–9. doi:10.1200/JCO.2007.14.9930

⁵ Venook AP, Niedzwiecki D, Lenz H-J, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA 2017; 317: 2392–401. doi:10.1001/jama.2017.7105

⁶ Lenz H-J, Van Cutsem E, Luisa Limon M, et al. First-line nivolumab plus low-dose Ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol 2022; 40: 161–70. doi:10.1200/JCO.21.01015

⁷ Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480: 480–9. doi:10.1038/nature10673

⁸ André T, Shiu K-K, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020; 383: 2207–18. doi:10.1056/NEJMoa2017699

⁹ Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018; 36: 773–9. doi:10.1200/JCO.2017.76.9901

¹⁰ Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18: 1182–91. doi:10.1016/S1470-2045(17)30422-9

¹¹ National Comprehensive Cancer Network, Inc. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2023. All rights reserved. Accessed June 27, 2023. to view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 2023.

¹² National Comprehensive Cancer Network, Inc. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.3.2023. All rights reserved. Accessed June 27, 2023. to view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 2023.

¹³ Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021; 398: 27–40. doi:10.1016/S0140-6736(21)00797-2

¹⁴ Kang Y-K, Chen L-T, Ryu M-H, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with Her2-negative, untreated, Unresectable advanced or recurrent gastric or Gastro-Oesophageal junction cancer (ATTRACTION-4): a randomised, Multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2022; 23: 234–47. doi:10.1016/S1470-2045(21)00692-6

¹⁵ Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med 2022; 386: 449–62. doi:10.1056/NEJMoa2111380

¹⁶ Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–55.

¹⁷ Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in Solid Tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–47. doi:10.1016/j.ejca.2008.10.026

¹⁸ US Department of Health and Human Services. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, Available: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf

¹⁹ Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25: 1346–55. doi:10.1093/annonc/mdu141

²⁰ Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377: 2103–14. doi:10.1016/S0140-6736(11)60613-2

²¹ Innocenti F, Ou F-S, Qu X, et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J Clin Oncol 2019; 37: 1217–27. doi:10.1200/JCO.18.01798

²² Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017; 376: 2415–26. doi:10.1056/NEJMoa1613493

²³ Lenz H-J, Ou F-S, Venook AP, et al. Impact of consensus molecular subtype on survival in patients with metastatic colorectal cancer: results from CALGB/SWOG 80405 (alliance). J Clin Oncol 2019; 37: 1876–85. doi:10.1200/JCO.18.02258

²⁴ Stintzing S, Wirapati P, Lenz H-J, et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. Ann Oncol 2019; 30: 1796–803. doi:10.1093/annonc/mdz387

²⁵ Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015; 21: 1350–6. doi:10.1038/nm.3967

²⁶ Fontana E, Eason K, Cervantes A, et al. Context matters—consensus molecular subtypes of colorectal cancer as biomarkers for clinical trials. Ann Oncol 2019; 30: 520–7.: S0923-7534(19)31131-7. doi:10.1093/annonc/mdz052

²⁷ Antoniotti C, Rossini D, Pietrantonio F, et al. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol 2022; 23: 876–87. doi:10.1016/S1470-2045(22)00274-1

²⁸ Tabernero J, Grothey A, Arnold D, et al. MODUL cohort 2: an adaptable, randomized, signal-seeking trial of fluoropyrimidine plus bevacizumab with or without atezolizumab maintenance therapy for BRAF(Wt) metastatic colorectal cancer. ESMO Open 2022; 7: 100559. doi:10.1016/j.esmoop.2022.100559

²⁹ Herting CJ, Farren MR, Tong Y, et al. A multi-center, single-arm, phase IB study of pembrolizumab (MK-3475) in combination with chemotherapy for patients with advanced colorectal cancer: HCRN Gi14-186. Cancer Immunol Immunother 2021; 70: 3337–48. doi:10.1007/s00262-021-02986-5