Abstract
Background:
Standard adjuvant chemotherapy for stage III colon cancer consists of a fluoropyrimidine plus oxaliplatin regimen. The phase 3 ATOMIC trial evaluated whether the addition of atezolizumab (anti-PD-L1) to modified FOLFOX6 (mFOLFOX6) improves outcomes in patients with stage III colon cancer with deficient mismatch repair (dMMR) status.
Methods:
Patients with resected stage III dMMR tumors were randomized (1:1) to receive adjuvant atezolizumab plus mFOLFOX6 for 6 months with atezolizumab continued as monotherapy (total 12 months) versus mFOLFOX6 for 6 months. The primary endpoint was disease-free survival; secondary endpoints were overall survival and adverse event profile.
Results:
Patients (n = 712) received atezolizumab plus mFOLFOX6 (n = 355) versus mFOLFOX6 (n = 357). Median age was 64 years, 55.1% were female, and 53.9% of tumors were T4, N2 or both. After a median follow-up of 40.9 months, the 3-year disease-free survival was 86.3% (95% CI, 81.8 to 89.9) in the atezolizumab plus mFOLFOX6 arm and 76.2% (95% CI, 70.9 to 80.6) in the mFOLFOX6 arm [hazard ratio (HR) for recurrence or death, 0.50; 95% CI, 0.35 to 0.73; P<0.0001]. Grade 3 and 4 adverse events occurred in 84.1% of patients in the atezolizumab plus mFOLFOX6 arm and 71.9% in the mFOLFOX6 arm.
Conclusion:
The addition of atezolizumab to mFOLFOX6 significantly improved disease-free survival in stage III dMMR colon cancer.
Introduction
Colorectal cancer is the third most common cancer and the second leading cause of cancer-related mortality worldwide.1 Evidence indicates that 10-15% of localized colon cancers show deficient DNA mismatch repair (MMR) that results in microsatellite instability-high (MSI-H) characterized by hypermutation immune checkpoint up-regulation, and abundant predicted neoantigens.2,3 The standard of care for patients with stage III colon cancer is upfront surgical resection followed by adjuvant chemotherapy with a fluoropyrimidine plus oxaliplatin regardless of MMR status. Adjuvant therapy is directed at eradicating micrometastatic disease; however, approximately 30% of stage III patients will experience recurrence despite such treatment.4,5 Colorectal cancer with dMMR has shown intrinsic resistance to fluoropyrimidines,6,7 but not to the combination of fluoropyrimidine plus oxaliplatin as shown in a pooled analysis of randomized adjuvant trials8. In patients with metastatic dMMR colorectal cancer which encompasses those with microsatellite instability (MSI-H), the immune checkpoint inhibitor pembrolizumab was shown to be superior to fluoropyrimidine-based chemotherapy where it produced significantly longer progression-free survival with fewer adverse events as first-line therapy (KEYNOTE-177).9
The phase 3 ATOMIC study was designed to investigate whether the addition of atezolizumab, an anti-PD-L1 antibody, to standard FOLFOX chemotherapy can improve disease-free survival in patients with curatively resected, dMMR stage III colon cancer.10 Atezolizumab binds PD-L1 preventing its engagement with PD-1 allowing cytotoxic T cells to attack tumor cells.11 In ATOMIC, patients received 6 months of adjuvant mFOLFOX6 without the possibility of 3 months of treatment, as the study was designed before results from the IDEA collaboration,12 and accrual was far along at the time of the IDEA publication.13 Participants in the ATOMIC trial were randomized (1:1) to treatment with atezolizumab plus mFOLFOX6 for 6 months with atezolizumab continued as monotherapy for an additional 6 months compared to mFOLFOX6 alone for 6 months. At the second prespecified interim analysis on February 4, 2025, the data safety monitoring board determined that the study had met its primary endpoint. The present report provides the first results for the primary disease-free survival endpoint.
Methods
Patients.
Eligible patients were ≥ 12 years of age with completely resected (R0), histologically confirmed, stage III colon adenocarcinoma (any T, N1-2 M0) and dMMR status determined by local site-directed immunohistochemistry or at a site-selected reference laboratory; retrospective central confirmation was also performed. Patients known to have the Lynch syndrome, based on information provided by the study sites, were eligible. An ECOG performance status of 0 to 2 (5-point scale; higher numbers reflect greater disability) was required. No prior chemotherapy or radiation was permitted except one cycle of mFOLFOX6 before enrollment to allow sufficient time to obtain MMR test results.
Trial Design and Treatment.
ATOMIC is an international, multicenter phase 3 trial conducted by the Alliance for Clinical Trials in Oncology, a member of the National Clinical Trials Network (NCTN) sponsored by the National Cancer Institute (NCI, NCT02912559). Patients were enrolled at NCTN and German Arbeitsgemeinschaft Internistische Onkologie (AIO) sites. Patients were randomized (1:1), via permuted block design with block size of 4, within 10 weeks after surgery to atezolizumab (840 mg intravenously every 2 weeks for 12 cycles) (6 months) plus modified (m) FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) followed by atezolizumab monotherapy for 13 cycles (12 months total) versus mFOLFOX6 [(5-fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours), oxaliplatin (85 mg/m2), and leucovorin (400 mg/m2)] alone for 12 cycles (6 months total). Stratification factors were N-stage (N1/N1c vs N2), T-stage (T1-T3 vs T4) and tumor sidedness (proximal vs distal to the splenic flexure) (see Supplementary Appendix).
Management of interruptions to treatment and dose reductions for chemotherapy were specified in the protocol. Reductions in atezolizumab doses were not allowed. Patients continued the trial regimen until protocol defined duration or until disease recurrence, metastasis, unacceptable AEs, withdrawal of consent, whichever occurred earlier. Evaluation for recurrent or metastatic disease was specified in the protocol and consistent with National Comprehensive Cancer Network (NCCN) guidelines.
Trial Oversight
The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the principles of the Declaration of Helsinki. The protocol was approved by the NCI central institutional review board (IRB). All the patients provided written informed consent before enrollment. The trial was regularly monitored by the Alliance Data and Safety Monitoring Board (DSMB), who also reviewed the prespecified interim analyses. Data were collected by the Alliance, reviewed by the trial chairperson, and analyzed in collaboration with the Alliance Statistics and Data Management Center. All authors contributed to the writing or critical review of the manuscript, vouch for the data and protocol adherence, and approved the final version. No one outside the author group contributed to manuscript writing.
Statistical Analysis
The primary endpoint was disease-free survival, defined as the time from randomization to disease recurrence or death from any cause. Secondary endpoints were overall survival and adverse events (NCI Common Terminology Criteria for Adverse Events [CTCAE], version 5.0). The secondary endpoints of patient-reported outcome-CTCAE (PRO-CTCAE) and quality of life will be reported separately. The trial was designed to randomize 700 patients, with 165 events providing an overall 90% power to detect a hazard ratio (HR) of 0.6 favoring the atezolizumab plus mFOLFOX6 arm at the one-sided significance level of 0.025. Interim analyses were planned at 50% (for efficacy and futility) and 75% (efficacy) of the projected disease-free survival events. The second interim efficacy two-sided boundary for disease-free survival is 0.0202. A gatekeeping procedure controlled the overall one-sided type I error of 0.025, permitting overall survival testing only if disease-free survival was statistically significant. For overall survival, approximately 163 events provide 90% power to detect a HR of 0.6 favoring the atezolizumab plus mFOLFOX6 arm (one-sided significance level of 0.025). The interim efficacy two-sided boundary is 0.0006. Although the protocol design and statistical analysis plan were based on one-sided testing, two-sided P values are reported.
Efficacy was assessed in the intent-to-treat (ITT) population, which included all randomized patients analyzed according to their assigned treatment. A post-hoc per-protocol analysis was performed among eligible patients who received any protocol therapy, had centrally confirmed dMMR, and were evaluated according to treatment received. Disease-free and overall survival were compared between treatment groups using stratified log-rank tests; their hazard ratios were estimated using a stratified Cox proportional-hazards model without covariates adjustment. Survival distribution was estimated using the Kaplan-Meier method. Stratification factors were applied to all stratified efficacy analyses. Confidence interval widths were not adjusted for multiplicity and should not be used in place of hypothesis testing.
Patients included in safety evaluations had received at least one dose of protocol treatment. Adverse events were graded and attributed by site investigators (protocol available with the full text of this article at NEJM.org). Statistical analyses were performed using SAS software, version 9.04 (SAS Institute).
Results
Patients
A total of 712 patients with dMMR stage III colon cancer were enrolled from 312 sites (303 NCTN, 9 AIO) and randomized (September 2017 to January 2023) to atezolizumab plus mFOLFOX6 (n = 355) versus mFOLFOX6 (n = 357) [Figure 1]. Median patient age was 64 years, 55.1% were female, and 83.7% had proximal tumors (Table 1). Overall, 46.1% had clinical low risk (T1-3N1) tumors and 53.9% had high risk (T4 and/or N2) tumors.13 Baseline characteristics and stratification variables were well balanced between study arms (Table 1 and Supplementary Table 2). The demographics of our study population are similar to those reported for stage III dMMR colon cancers identified from the National Cancer Database14 [Supplementary Table 3]. As of the cutoff date (February 4, 2025), all patients had discontinued treatment. Among the ITT population, 99.4% had dMMR tumors by local IHC testing Retrospective central confirmation of dMMR status was achieved in 91.4% of patients using submitted tissue (n = 689) (Table 1).
Figure 1:
CONSORT Diagram
Table 1:
Patient Clinical and Pathological Features
| Arm 1 (Atezolizumab + mFOLFOX6) (N=355) | Arm 2 (mFOLFOX6) (N=357) | Total (N=712) | |
|---|---|---|---|
| Patient Accrual^, n (%) | 341 (96.1%) | 343 (96.1%) | 684 (96.0%) |
| Age (years), Median (IQR) | 64.0 (50.0, 72.0) | 63.0 (47.0, 72.0) | 64.0 (49.0, 72.0) |
| Female Sex, n (%) | 186 (52.4%) | 206 (57.7%) | 392 (55.1%) |
| T-Stage, n (%) | |||
| T1 | 11 (3.1%) | 4 (1.1%) | 15 (2.1%) |
| T2 | 30 (8.5%) | 22 (6.2%) | 52 (7.3%) |
| T3 | 202 (56.9%) | 216 (60.5%) | 418 (58.7%) |
| T4 | 112 (31.5%) | 114 (31.9%) | 226 (31.7%) |
| Tx | 0 (0.0%) | 1 (0.3%) | 1 (0.1%) |
| N stage, n (%) | |||
| N1/N1c | 226 (63.7%) | 225 (63.0%) | 451 (63.3%) |
| N2 | 129 (36.3%) | 132 (37.0%) | 261 (36.7%) |
| Clinical Risk Group*, n (%) | |||
| High (T4 and/or N2) | 191 (53.8%) | 193 (54.1%) | 384 (53.9%) |
| Low (Tx-T3 and N1/N1c) | 164 (46.2%) | 164 (45.9%) | 328 (46.1%) |
| ECOG Performance Status†, n (%) | |||
| 0 | 238 (67.0%) | 225 (63.0%) | 463 (65.0%) |
| 1 | 111 (31.3%) | 127 (35.6%) | 238 (33.4%) |
| 2 | 6 (1.7%) | 5 (1.4%) | 11 (1.5%) |
| Lynch Syndrome, n (%) | |||
| Yes | 71 (20.0%) | 79 (22.1%) | 150 (21.1%) |
| No | 232 (65.4%) | 227 (63.6%) | 459 (64.5%) |
| Unknown | 52 (14.6%) | 51 (14.3%) | 103 (14.5%) |
| Central MMR Status#, n (%) | |||
| MMR-deficient | 324 (92.8%) | 306 (90.0%) | 630 (91.4%) |
| MMR-proficient | 20 (5.7%) | 22 (6.5%) | 42 (6.1%) |
| Inconclusive | 5 (1.4%) | 12 (3.5%) | 17 (2.5%) |
| Missing | 6 | 17 | 23 |
Including one pediatric patient randomized to atezolizumab plus mFOLFOX6
Post-hoc analysis
Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 to 5; higher status indicating greater disability).Lansky-Play performance status of 100 from one patient <16 years old was converted to ECOG PS of 0.
Retrospective central confirmation; missing indicates that no specimen was submitted for central confirmation.
Treatment completion rates are shown in Figure 1. In the atezolizumab plus mFOLFOX6 arm, five (1.4%) patients never began protocol treatment, 163 (45.9%) completed protocol treatment, and 187 (52.7%) discontinued early, most commonly due to withdrawal during treatment (n=76; 21.4%) or adverse events (n=62; 17.5%). In the mFOLFOX6 alone arm, 27 (7.6%) never began protocol treatment, 214 (59.9%) completed treatment, and 116 (32.5%) discontinued early due to withdrawal (n=51, 14.3%) or adverse events (n=32, 9.0%) [Supplementary Table 4]. Disease recurrence during protocol treatment occurred in 5 patients (1.4%) in the atezolizumab plus mFOLFOX6 arm and in 13 patients (3.6%) in the mFOLFOX6 arm. Withdrawal and adverse event discontinuation rates were similar during the first 6 months of treatment, but their rates were higher beyond 6 months during atezolizumab monotherapy. (Supplementary Table 4).
Efficacy
At the data cutoff date, 127 total disease-free survival events (Arm 1: 46; Arm 2: 81) occurred at a median follow-up of 40.9 months (interquartile range [IQR], 26.7 to 58.6). Disease-free survival at 3 years was 86.3% (95% CI, 81.8 to 89.8) for atezolizumab plus mFOLFOX6 compared to 76.2% (95% CI, 70.9 to 80.6) for mFOLFOX6 (stratified HR, 0.50; 95% confidence interval [CI] , 0.35 to 0.73) [Figure 2]. The stratified log-rank p-value was 0.0002. In an analysis of disease-free survival in patients who had central confirmation of their tumor dMMR status (n=630) similar results were found [Supplementary Figure 1]. In a post hoc analysis of the per-protocol population (n = 600), results were consistent with the primary analysis (Supplementary Figure 2). The efficacy of atezolizumab plus mFOLFOX6 across prespecified subgroups is shown in Figure 3. In a pre-specified subgroup analysis, we examined the duration of adjuvant chemotherapy in relationship to patient disease-free survival. When stratified by duration of mFOLFOX6 treatment, an apparent disease-free survival benefit for atezolizumab was observed among patients who received more than six cycles of mFOLFOX6 (HR 0.41, 95% CI 0.27–0.64), whereas no advantage was seen in those who received ≤6 cycles (HR 0.97, 95% CI 0.44–2.11).
Figure 2:
Disease-free Survival (DFS) by Study Arm among All Randomized Stage III Colon Cancer Patients
Figure 3:
DFS for Patient Subgroups by Study Arm
As of the data cutoff date with a median follow-up for overall survival of 45.8 months (IQR 32.0 to 64.7), 31 events occurred in the atezolizumab plus mFOLFOX6 arm and 33 events occurred in the mFOLFOX6 arm. Overall survival showed no statistically significant difference by study arm (stratified log-rank p value of 0.6787). The 5-year overall survival rate was 89.7% (95% CI, 85.2 to 92.9) for atezolizumab plus mFOLFOX6 versus 87.9% (95% CI, 83.1 to 91.4) for mFOLFOX6 alone (stratified HR, 0.90; 95% CI, 0.55 to 1.47) (Supplementary Figure 3).
Exposure and Safety
Randomized patients who received ≥1 dose of protocol therapy were evaluated for drug exposure and safety. Among patients in the atezolizumab plus mFOLFOX6 arm (n =350), the median duration of mFOLFOX6 was 5.4 months (IQR, 4.7 to 5.8), and was 10.8 months (IQR, 4.7 to 11.8) for atezolizumab (Supplementary Table 5). In the mFOLFOX6 arm (n =330), the median treatment duration was also 5.4 months (IQR, 3.8 to 5.8). Drug exposure, median number of cycles and the median percent dose received, and median treatment duration for bolus fluorouracil, infusion fluorouracil, and oxaliplatin were similar between arms (Supplementary Table 5).
Adverse events were assessed in 346 patients in the atezolizumab–mFOLFOX6 group and 334 in the mFOLFOX6 group (including 4 patients randomized to atezolizumab who never received it).
Among all adverse events, the incidence of any grade adverse events was similar between study arms (100% vs 98.5%) (Table 2). Regardless of attribution, any grade 3 and 4 events were more frequent with atezolizumab plus mFOLFOX6 arm (84.1% vs. 71.9%), with higher rates of non-hematologic toxicities (69.4% vs. 54.5%), including fatigue (10.1% vs. 3.3%) [Table 2]. Hematological toxicities that were grade 3 and 4 were seen in 46.8% of patients in the atezolizumab plus mFOLFOX6 arm compared to 38.6% in the mFOLFOX6 arm. A higher rate of grade 3 and 4 neutrophil count decrease occurred more frequently in patients in the atezolizumab plus mFOLFOX6 arm (43.6% vs 35.9%).
Table 2:
Selected Adverse Events in All Treated Patients
| Arm 1 (Atezolizumab + mFOLFOX6) (N=346) | Arm2 (mFOLFOX6) § (N=334) | |||
|---|---|---|---|---|
| Any Grade n (%) | Grade 3 and 4 n (%) | Any Grade n (%) | Grade 3 and 4 n (%) | |
| Any AE | 346 (100) | 291 (84.1) | 329 (98.5) | 240 (71.9) |
| Hematological | 312 (90.2) | 162 (46.8) | 293 (87.7) | 129 (38.6) |
| Non-Hematological | 346 (100) | 240 (69.4) | 329 (98.5) | 182 (54.5) |
| Common events * | ||||
| Fatigue | 322 (93.1) | 35 (10.1) | 294 (88) | 11 (3.3) |
| Peripheral sensory neuropathy | 266 (76.9) | 64 (18.5) | 234 (70.1) | 50 (15) |
| Nausea | 265 (76.6) | 16 (4.6) | 232 (69.5) | 3 (0.9) |
| Neutrophil count decreased | 255 (73.7) | 151 (43.6) | 226 (67.7) | 120 (35.9) |
| Diarrhea | 251 (72.5) | 42 (12.1) | 206 (61.7) | 28 (8.4) |
| Platelet count decreased | 236 (68.2) | 7 (2) | 223 (66.8) | 12 (3.6) |
| Abdominal pain | 172 (49.7) | 17 (4.9) | 120 (35.9) | 7 (2.1) |
| Anorexia | 172 (49.7) | 7 (2) | 132 (39.5) | 0 (0) |
| Anemia | 160 (46.2) | 13 (3.8) | 149 (44.6) | 11 (3.3) |
| Cough | 152 (43.9) | 1 (0.3) | 81 (24.3) | 0 (0) |
| White blood cell decreased | 136 (39.3) | 26 (7.5) | 134 (40.1) | 8 (2.4) |
| Dyspnea | 130 (37.6) | 6 (1.7) | 84 (25.1) | 4 (1.2) |
| Aspartate aminotransferase increased# | 124 (35.8) | 11 (3.2) | 119 (35.6) | 3 (0.9) |
| Mucositis oral | 122 (35.3) | 9 (2.6) | 116 (34.7) | 4 (1.2) |
| Alkaline phosphatase increased | 106 (30.6) | 3 (0.9) | 101 (30.2) | 0 (0) |
| Alanine aminotransferase increased# | 103 (29.8) | 7 (2) | 85 (25.4) | 3 (0.9) |
| Hypokalemia | 89 (25.7) | 32 (9.2) | 71 (21.3) | 15 (4.5) |
| Vomiting | 89 (25.7) | 10 (2.9) | 66 (19.8) | 4 (1.2) |
| Fever | 73 (21.1) | 0 (0) | 25 (7.5) | 1 (0.3) |
| Lymphocyte count decreased | 72 (20.8) | 9 (2.6) | 46 (13.8) | 3 (0.9) |
| Hyperglycemia# | 71 (20.5) | 9 (2.6) | 34 (10.2) | 4 (1.2) |
| Hypothyroidism# | 69 (19.9) | 0 (0) | 13 (3.9) | 0 (0) |
| Pruritus | 58 (16.8) | 2 (0.6) | 20 (6) | 0 (0) |
| Hypertension | 57 (16.5) | 27 (7.8) | 56 (16.8) | 39 (11.7) |
| Rash maculo-papular# | 49 (14.2) | 3 (0.9) | 20 (6) | 0 (0) |
| Colitis† | 23 (6.6) | 4 (1.2) | 2 (0.6) | 0 (0) |
| Adrenal insufficiency† | 4 (1.2) | 3 (0.9) | 0 (0) | 0 (0) |
Adverse events reported ≥15% of randomized patients (received at least one dose of protocol treatment) in either study arm.
Potential immune-related AEs
Potential immune-related AEs reported in <15% of randomized patients in each study arm.
Safety data from 4 patients who were randomized to atezolizumab plus mFOLFOX6 arm but did not receive atezolizumab were included in the mFOLFOX6 arm.
We then examined adverse events in all patients in the atezolizumab plus mFOLFOX6 arm by treatment phase (atezolizumab with vs without mFOLFOX6). In the atezolizumab plus mFOLFOX6 arm, grade 3 and 4 fatigue occurred in 4.0% of patients during combination therapy and in 6.1% during atezolizumab monotherapy (Supplementary Table 6). Neutropenia occurred in 30.1% of patients in the atezolizumab plus mFOLFOX6 arm during the first 6 months (35.9% in the mFOLFOX6-alone arm), and in 13.6% of patients during the subsequent 6-month atezolizumab monotherapy phase. Increases of more than 5% in suspected immune-related adverse events such as hypothyroidism, hyperglycemia, colitis, and rash were more frequent with atezolizumab plus mFOLFOX6, although the rates of grade 3 and 4 adverse events were not clinically significant and similar between arms (Table 2).
Treatment-related grade 3 and 4 adverse events occurred in 72.5% of patients in the atezolizumab plus mFOLFOX6 arm compared with 61.7% in the mFOLFOX6 arm (Supplementary Table 7). Grade 3 and 4 treatment-related non-hematological toxicities were seen in 53.8% of patients in the atezolizumab plus mFOLFOX6 arm compared to 38.6% in the mFOLFOX6 arm. We observed higher rates of grade 3 and 4 treatment-related fatigue (9.0% vs. 3.3%) and neutrophil count decrease (40.5% vs. 34.7%) in the atezolizumab-containing arm. [Supplementary Table 7]. Analysis of treatment-related grade 3 and 4 fatigue and neutrophil count decrease by treatment phase (atezolizumab with vs without mFOLFOX6) showed similar results as was observed for these adverse events without attribution (Supplementary Tables 7,8).
Among all adverse events regardless of attribution, grade 5 events (deaths) occurred in six patients in the atezolizumab plus mFOLFOX6 arm and in two patients in the mFOLFOX arm. Two of the deaths in the atezolizumab plus mFOLFOX6 arm were deemed treatment-related: sudden death and sepsis. The other 4 deaths (death not otherwise specified, myocardial infarction, colonic obstruction, and sudden death) in the atezolizumab plus mFOLFOX6 arm were not considered to be treatment related. In the mFOLFOX6 arm, both grade 5 events (two occurrences of cardiac arrest) were deemed unrelated to study treatment.
Discussion
In this phase 3 randomized trial, the addition of atezolizumab to mFOLFOX6 significantly improved disease-free survival as compared with mFOLFOX6 alone in patients with resected, dMMR stage III colon cancer. The addition of atezolizumab to mFOLFOX6 was associated with a ten percentage point absolute reduction and a 50% reduction in the hazard of disease recurrence or death compared to mFOLFOX6 alone. No difference in overall survival has been observed between the study arms at this first analysis with a median follow-up of 40.9 months, and longer follow-up is required for mature estimates. Because patients in both arms are expected to receive standard-of-care immunotherapy if they develop metastases, any future overall survival differences may be difficult to interpret. Limited data were collected on subsequent therapy: among 81 disease-free survival events in the mFOLFOX6 arm, 71 were recurrences; of these, 61 received further systemic therapy and 51 (83.6%) received immunotherapy.
With regard to mFOLFOX6 exposure, the median number of cycles and the median percent dose received were similar by study arm for 5-fluorouracil (5-FU) bolus, 5-FU infusion as well as for oxaliplatin indicating that no reduction in chemotherapy exposure was associated with the addition of atezolizumab. Overall, adverse events were consistent with the known safety profile of the study drugs. While a higher rate of non-febrile neutropenia was noted in the atezolizumab plus mFOLFOX6 arm, analysis of adverse events by treatment phase showed similar rates of neutropenia between arms when both arms received mFOLFOX6. In the mFOLFOX6 alone control arm, the rate of neutropenia was similar to that observed for this regimen in the NSABP C-08 adjuvant trial (35.9% vs 32.6%).17 Among suspected immune-related adverse events in the atezolizumab plus mFOLFOX6 arm, we observed a ≥ 5% increase in any grade hyperglycemia, hypothyroidism, colitis, and maculopapular rash; however, no corresponding increase in immune-related grade 3 and 4 events was observed with the addition of atezolizumab to mFOLFOX6.
ATOMIC evaluated 12 months of adjuvant atezolizumab based on pivotal melanoma trial data showing durable survival benefit with one year of checkpoint inhibition,18 and current regulatory approvals for adjuvant immune checkpoint inhibitor therapy specify a treatment duration of one year. ATOMIC was not designed to test the benefit of atezolizumab in the absence of standard chemotherapy. While colon cancers with dMMR have shown resistance to fluoropyrimidines,6 a benefit of oxaliplatin is suggested by data from a retrospective, observational cohort study19 and a pooled analysis.8 At the time ATOMIC was developed, adjuvant mFOLFOX6 for 12 cycles (6 months) was the standard of care for stage III colon cancer and was chosen as the control arm. In a pre-specified subgroup analysis, a disease-free survival benefit with atezolizumab was observed among patients who received more than six cycles (3 months) of mFOLFOX6 (HR, 0.41; 95% CI, 0.27–0.64), whereas no disease-free survival advantage was seen in those who received ≤6 cycles (HR, 0.97; 95% CI, 0.44–2.11). These exploratory findings suggest, but do not prove, that the therapeutic benefit of adjuvant atezolizumab may depend on adequate chemotherapy exposure.
Despite the marked improvement observed for disease-free survival, nearly 14% of participants who received atezolizumab plus mFOLFOX6 had recurrence or death at 3 years indicating the presence of intrinsic resistance to the PD-L1 inhibitor. Mechanisms of resistance against immune checkpoint inhibitors include decreased immunogenicity, defects in antigen presentation or interferon gamma signaling, and increased activation of Wnt signaling as shown in biospecimens from metastatic dMMR CRCs from the Keynote-177 study that compared pembrolizumab to standard chemotherapy.20
In patients with stage II and III dMMR colon cancers, studies of neoadjuvant immune checkpoint inhibitor therapy, including the NICHE-2 trial,21 have shown high rates of pathological response.22,23 Both the ATOMIC trial and the NICHE-2 trial21 represent two strategies for the treatment of dMMR colon cancer, i.e, surgery followed by FOLFOX plus atezolizumab or neoadjuvant combination immune checkpoint inhibitors followed by surgery. The studies are not directly comparable in that ATOMIC is a randomized phase 3 trial whereas NICHE-2 is a single-arm study that enrolled a selected patient cohort, reported a low event rate, and faced inherent challenges with accurate radiographic tumor staging.21 Patients with dMMR tumors are more likely to have an increased number and size of regional lymph nodes with the potential for overstaging and over-treatment.24 Results are awaited from the ongoing phase 3 AZUR-2 trial, which compares neoadjuvant dostarlimab (anti–PD-1) followed by surgery and six months of adjuvant dostarlimab versus upfront surgery followed by a fluoropyrimidine plus oxaliplatin.24
In conclusion, the addition of atezolizumab to mFOLFOX6 resulted in a significant reduction in recurrence or death indicating it is an effective adjuvant treatment of patients with resected dMMR stage III colon cancer. The trial was conducted across 303 NCTN sites in the United States and AIO sites in Germany, most of which were community-based practices, and no upper age limit was applied, supporting the generalizability of the findings. Baseline demographic and clinical features were also similar to those of a large NCDB cohort of patients with dMMR stage III colon cancer,14 further reinforcing the representativeness of the study population. The ATOMIC results have been incorporated into the most recent NCCN guidelines,25 which also extend these findings to T4bN0 stage II cancers. These findings support universal MMR testing in all patients with newly diagnosed colon cancer, both to identify the Lynch syndrome and to determine eligibility for immunotherapy.
Supplementary Material
Support:
This manuscript is the result of funding in whole or in part by the National Cancer Institute of the National Institutes of Health (NIH) under Award Numbers U10CA180821 and U10CA180882, and U24CA196171; (to the Alliance for Clinical Trials in Oncology); UG1CA233253, UG1CA189816, UG1CA189830, UG1CA189953, UG1CA189971, UGICA232760, UG1CA233180, UG1CA233290, UG1CA233184, UG1CA233331; U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG Oncology); U10CA180886 (COG); and U10CA180888 (SWOG). Also supported in part by funds from Genentech, a member of the Roche group. It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make the Author Accepted Manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. https://acknowledgments.alliancefound.org.
(Funded by the National Cancer Institute of the National Institutes of Health (NIH); Trial Reg NCT02912559)
Footnotes
Clinicaltrials.gov Identifier: NCT02912559
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
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