Pretreatment With Temozolomide, Immunotherapy Combo Elicits Encouraging Responses in MSS and MGMT-Silenced mCRC

The addition of temozolomide to a low-dose treatment plan of ipilimumab and nivolumab extended progression-free survival among patients with metastatic colorectal cancer.

Patients with microsatellite stable (MSS) and MGMT-silenced metastatic colorectal cancer (mCRC) experienced priming clinical benefit after receiving treatment with temozolomide priming followed by the combination of low-dose ipilimumab (Yervoy) and nivolumab (Opdivo), according to data from the phase 2 MAYA trial published in the Journal of Clinical Oncology.1

The trial met its primary end point by demonstrating that the 9-month progression-free survival (PFS) rate among participants was 36% (95% CI, 23%-57%). At a median follow-up of 23.1 months (interquartile range, 14.9-24.6), 12 out of 33 patients achieved a PFS that was longer than 8 months.

In addition, trial participants achieved a median PFS of 7.0 months (95% CI, 5.5-8.3), and a median overall survival (OS) of 18.4 months (95% CI, 14.9–nonassessable). At a 12-month follow-up, the PFS rate was 24% (95% CI, 13%-44%), and at an 18-month follow-up, the PFS rate was 20% (95% CI, 10%-41%).

““The MAYA study provided evidence on the role of temozolomide as an immune-sensitizing agent for MSS and immune-cold mCRCs selected by the presence of MGMT silencing and disease control on temozolomide priming,” lead study author Federica Morano, MD, of the Department of Medical Oncology at the Fondazione IRCCS Istituto Naziionale dei Tumori, and colleagues, wrote in the paper. “Further investigation is warranted to optimize the molecular and clinical selection of patients eligible for this therapeutic approach with the aim of maximizing its success rate.”

The oral alkylating agent temozolomide is approved for the treatment of patients with glioblastoma, and its efficacy is associated with the predictive biomarker, MGMT promoter methylation. Because MGMT plays a role in the repair of DNA damage that is caused by alkylating agents, it is known that epigenetic MGMT silencing represents a mechanism of synthetic lethality following temozolomide exposure.

Although tumor responses to temozolomide are restricted to those with concomitant lack of MGMT protein expression, complete MGMT silencing at both the gene and protein level as well as proficient mismatch repair/MSS status, are needed but are not sufficient to adequately predict for response or benefit that will be derived with the agent.

Investigators hypothesize that acquired resistance to the drug could be linked with the onset of hypermutation with a certain genomic scar that is defined by C>T transitions and the frequent emergence of secondary mutations in MSH6 and other MMR genes. Evidence of this effect has been described in hypermutated relapses of glioblastoma, and in both models of CRC and patients with mCRC. MAYA was launched to provide clinical validation of this hypothesis.

The trial enrolled those with histologically confirmed metastatic and inoperable adenocarcinoma of the colon or rectum who were 18 years of age or older, had an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria. Patients also needed to have progressive disease, or a contraindication to irinotecan, fluoropyrimidines, irinotecan, and anti-EGFR drugs.

Moreover, patients needed to also have centrally confirmed MSS status per multiplex polymerase chain reaction, MGMT promoter methylation per pyrosequencing, and MGMT absent expression per immunohistochemistry.

In the first treatment portion of the trial, 135 study participants were given oral temozolomide monotherapy at a once-daily dose of 150 mg/m2 on days 1 through 5, once every 4 weeks, for 2 cycles. By week 7 plus or minus 5 days, patients then underwent radiologic assessment per RECIST v1.1 criteria and blinded independent central review (BICR). Patients who were found to achieve a complete response (CR), a partial response (PR), or stable disease, then went onto the second treatment portion of the trial.

In this portion of the research, 33 participants received temozolomide at the same dose and schedule paired with a flat intravenous (IV) dose of nivolumab, given at 480 mg once every 4 weeks, and low-dose ipilimumab at an IV dose of 1 mg/kg once every 8 weeks. Here, patients received treatment until disease progression per RECIST v1.1 criteria, intolerable toxicity, withdrawn consent, death, or immune-related RECIST (ir-RECIST) progressive disease.

The primary end point of the trial was the 8-month PFS rate per investigator assessment in those who started the second treatment portion of the trial. Key secondary end points included PFS, OS, objective response rate (ORR) per RECIST v1.1 and ir-RECIST criteria, duration of response (DOR), safety, and quality of life. Other end points included BICR-assessed PFS, ORR, and DOR.

At a data cutoff date for the research was December 17, 2021, the median number of immunotherapy cycles received was 7 (range, 1-26). Moreover, a total of 26 RECIST v1.1 PFS events were reported, as well as 23 ir-RECIST PFS events. Seventeen deaths had occurred.

Regarding baseline characteristics, 72% of patients had RAS-mutated tumors, which proved to be consistent with the profile of MGMT hypermethylation. Fifty-five percent of patients had received 3 or more prior lines of treatment.

“When comparing patients with or without clinical benefit after temozolomide priming, no statistically significant differences were observed, except for lower median age and higher frequency of right-sidedness in patients who started the second treatment,” the study authors wrote.

Additional findings showed that the approach elicited an ORR of 45% (95% CI, 29%-62%) according to RECIST v1.1 criteria; this included 15 PRs and no CRs. Seventy-nine percent of patients experienced tumor shrinkage. When looking specifically at those included in the second treatment portion of the research, the ORR was found to be 18% (95% CI, 9%-34%). Moreover, the median DOR per RECIST v1.1 criteria was 4.8 months (95% CI, 3.8–nonassessable).

Regarding safety in the first treatment portion of the research, 53% of the 135 patients experienced any-grade adverse effects (AEs) associated with temozolomide; 3% of these effects were grade 3 or higher in severity. The most frequently experienced toxicities were noted to be hematologic and gastrointestinal effects. In the second portion of the research, 91% of patients experienced any-grade AEs and 21% experienced effects that were grade 3 or higher.

Immune-related effects included skin rash (any grade, 18%; grade 3 or higher, 6%), colitis (18%; 3%), hypothyroidism (21%; 0%), hyperthyroidism (9%; 0%), hypophysitis (6%; 3%), and adrenal insufficiency (3%; 0%).

“Our results represent the clinical transition of seminal efforts carried out in CRC models and patients and in other temozolomide-sensitive cancers,” the study authors concluded.

Reference

  1. Morano F, Raimondi A, Pagani F, et al. Temozolomide followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite-stable, O6-methylguanine-DNA methyltransferase-silenced metastatic colorectal cancer: the MAYA trial. J Clin Oncol. Published online March 8, 2022. doi:10.1200/JCO.21.02583

This article was originally published on OncLive as “Temozolomide Followed by Low-Dose Ipilimumab/Nivolumab Shows Potential in MSS and MGMT-Silenced mCRC”