Neoadjuvant IO Works Its Way Into Practice for GI Cancers

Andrea Cercek, MD

Neoadjuvant immunotherapy has already established benefit in tumor types such as melanoma and is now being considered for patients with gastrointestinal cancers. This approach has shown benefit for patients with rectal cancer as well as for those with colorectal cancer.

A well-received presentation from the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting that could alter standard practice for patients with rectal cancer highlighted a phase 2 trial (NCT04165772) for dostarlimab-gxly (Jemperli) for the treatment of patients with mismatch repair–deficient stage II or stage III rectal adenocarcinoma prior to chemoradiation and surgery.¹

In August 2021, dostarlimab was approved for the treatment of adult patients with mismatch repair–deficient (MRD) recurrent or advanced solid tumors.² In rectal cancer specifically, MRD is reported in approximately 5% to 10% of all cases, which usually indicates that the tumor would be resistant to chemotherapy treatment.³

The phase 2 study explored a possible earlier use for the treatment in the neoadjuvant setting for patients with earlier-stage MRD rectal cancer. Findings were also published in the New England Journal of Medicine.⁴

As of the data cutoff, 18 patients were treated in the study. The majority were women (67%) and White non-Hispanic individuals (61%), with T3 or T4 stage (78%), node-positive disease (94%), and a mutation in MSH2, MLH1, MSH6, or PMS2 (59%). All patients were BRAF V600E wild type. The median age of study participants was 54 years (range, 26-78).¹

Patients received intravenous dostarlimab at 500 mg every 3 weeks for 6 months, followed by standard radiation of 5040 cGy and concurrent capecitabine prior to total mesorectal excision.

The primary end point was sustained clinical complete response at 12 months or pathologic complete response and overall response rate. Secondary end points included safety and tolerability.

Fourteen patients were evaluable as of data cutoff, with a median follow-up of 6.8 months (range, 0.7-23.8). All patients achieved a clinical complete response for an overall response rate of 100%. Seven patients had a duration of response lasting more than 12 months, and 4 had responses lasting more than 24 months.¹

Clinical complete responses were observed as early as 3 months for 3 patients, but most were reported at 6 months.

“What I’d like to highlight is that the majority of these patients had big bulky tumors, [with] 94% node positive,” Andrea Cercek, MD, said during the ASCO presentation. “The standard of care for these patients would have very likely required all 3 modalities—chemotherapy, radiation, and surgery.”

Cercek is the section head of colorectal cancer and codirector of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center in New York, New York.

With these complete responses, no patients required subsequent chemotherapy, radiation, or surgery, and no disease recurrence was observed during the study’s follow-up period. Additionally, no grade 3 or 4 adverse events were reported.

“Longer follow-up is certainly required to establish the durability of this treatment,” Cercek said. “In conclusion, we believe these data provide the framework for immunoablative therapies. [They highlight] the clinical impact of biomarker-driven therapy—in other words, of moving precision medicine into early-stage disease. This has the potential to be translated rapidly into areas where access to modern chemotherapy and, even more importantly, radiation and surgery may not be available.”

Kimmie Ng, MD, MPH, a discussant for the ASCO presentation, agreed. “Neoadjuvant dostarlimab for 6 months represents a promising new treatment for patients with stage II/III [MRD] rectal cancer, [and] larger multicenter clinical trials with longer follow-up and disease-free survival and overall survival end points are needed,” she said.

“It is going to be critical that we identify predictive biomarkers of pathologic complete response to help guide the treatment for our patients.” Ng is director of translational research for the Division of Gastrointestinal Oncology and codirector of the Colon and Rectal Cancer Center at Dana-Farber Cancer Institute in Boston, Massachusetts.

Ng noted that other case studies have shown a benefit for neoadjuvant immunotherapy for patients with MRD rectal cancer but that further study is warranted before these data can truly be practice changing.

Colorectal Cancer

Neoadjuvant immunotherapy is also being investigated for and showing benefit in other gastrointestinal cancers. Final data were presented at the 2022 ASCO meeting from the NICHE trial (NCT03026140) for neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) for patients with nonmetastatic colorectal adenocarcinoma.⁵

Patients were divided into cohorts based on MRD (n = 32) and mismatch repair–proficient (MRP; n = 33) status; those with MRP disease also received celecoxib (Celebrex). Those with MRD status tended to be younger, with a median age of 54 years, and most had right-sided disease (62%), more advanced disease (T4, 47%), and node-positive disease (78%). In the MRP group, patients had a median age of 62 years, and most had left-sided disease (70%), lower-stage disease (T3, 58%), and node-negative disease (61%).

In the MRD cohort, 97% of patients had a major pathologic response and the remaining 3% had a partial pathologic response, for an overall response rate of 100%. All those with Lynch syndrome had a major response. Two patients received adjuvant chemotherapy. The median follow-up time in this cohort was 32 months with no recurrences to date.⁵

In the MRP group, 23% of patients had a major pathologic response and 6% had a partial response. Seventy-one percent of patients did not respond to the triplet regimen. Eight patients received adjuvant chemotherapy. The median follow-up time in this cohort was 28 months, and by this point, 2 patients had disease recurrence.

In the NICHE-2 study (EudraCT 016-002940-17) presented at the European Society for Medical Oncology Congress 2022, nivolumab and ipilimumab were further investigated as neoadjuvant therapy for patients with MRD nonmetastatic colorectal cancer.⁶

A total of 112 patients were enrolled with a median age of 60 years (range, 20-82); most patients had an ECOG performance status of 0 (87%), were women (58%), and had high-risk disease (74%) and right-sided disease (68%). Thirty-one percent of patients had Lynch syndrome.

Ninety-five percent of patients had a major pathologic response, including a pathologic complete response in 67%, and 4% had a partial response. Only 1 patient did not respond to the immunotherapy doublet. Pathologic complete response was reported in 78% of patients with Lynch syndrome and in 58% of patients with sporadic tumors (P = .056). At a median follow-up of 13.1 months, no disease recurrences were reported.⁶

_REFERENCES:

_{1. Cercek A, Lumish MA, Sinopoli JC, et al. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol. 2022;40(suppl 17):LBA5. doi:10.1200/JCO.2022.40.17_suppl.LBA5}

_{2. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated February 1, 2022. Accessed November 23, 2022. bit.ly/3whe2C6}

_{3. Cercek A, Dos Santos Fernandes G, Roxburgh CS, et al. Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clin Cancer Res. 2020;26(13):3271-3279. doi:10.1158/1078-0432.CCR-19-3728}

_{4. Cercek A, Lumish MA, Sinopoli JC, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445}

_{5. Verschoor YL, van den Berg J, Beets G, et al. Neoadjuvant nivolumab, ipilimumab, and celecoxib in MMR-proficient and MMR-deficient colon cancers: final clinical analysis of the NICHE study. J Clin Oncol. 2022;40(suppl 16):3511. doi:10.1200/JCO.2022.40.16_suppl.3511}

_{6. Chalabi M, Verschoor YL, van den Berg J, et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}