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Expert Analysis: CCO Independent Conference Highlights of the 2022 ASCO Gastrointestinal Cancers Symposium (GICS)
  • CME

Manish A. Shah, MD
Rachna Shroff, MD
Released: April 20, 2022

Key Studies in Rectal Cancer

Rationale for Early Use of Immunotherapy

Manish A. Shah, MD:
For locally advanced rectal cancer, particularly node-positive disease, the standard of care is preoperative CT and radiation followed by surgery and then more CT. However, patients with MMRd colorectal cancer have a poor response to neoadjuvant CT. There is a need for novel treatment approaches in these patients, and at ASCO GICS 2022, we saw an early report from a study investigating the use of PD-1 blockade in MMRd rectal cancer in the neoadjuvant setting.

Neoadjuvant PD-1 Blockade in Advanced MMRd Rectal Adenocarcinoma: Study Design

Manish A. Shah, MD:
Lumish and colleagues1 presented a study investigating the efficacy of neoadjuvant PD-1 blockade in advanced MMRd rectal adenocarcinoma (NCT04165772). This was a nonrandomized, prospective, single-arm phase II trial that enrolled adults with stage II and III MMRd rectal cancer and no distant metastases.

Patients received the PD-1 inhibitor dostarlimab at a dose of 500 mg IV every 3 weeks for up to 6 months, and they also could receive CT (capecitabine) with radiation, but that was not required. Tumors were assessed with imaging at baseline, 3 months, and 6 months. Endoscopic evaluation was performed at baseline, 6 weeks, 3 months, and 6 months. If a clinical CR was achieved after preoperative therapy, patients could continue with nonoperative management without any further treatment.

The coprimary endpoints in this trial were objective response rate (ORR) and pathologic CR or clinical CR at 12 months.

Neoadjuvant PD-1 Blockade in Advanced MMRd Rectal Adenocarcinoma: Efficacy Summary

Manish A. Shah, MD:
Most (77%) patients enrolled in this study were female, and the median age was 52 years (range: 26-78).1 Enrolled patients all had advanced rectal cancer, and 92% had nodal-positive disease by rectal MRI.

This study is ongoing, and so far 13 patients have been enrolled. In total,12 patients underwent at least a 3-month evaluation, and all 12 have achieved a clinical CR, making the ORR 100%. In total, 7 patients completed induction therapy, and all 7 achieved a clinical CR and are currently under observation without chemoradiation or surgery. At the time of this report, no patients in this trial had PD.

Neoadjuvant PD-1 Blockade in Advanced MMRd Rectal Adenocarcinoma: Conclusions

Manish A. Shah, MD:
The investigators concluded that neoadjuvant PD-1 blockade with single-agent dostarlimab in locally advanced MMRd rectal cancer appears to provide patients with circumvention of chemoradiotherapy and surgery. Of importance, no safety concerns were reported in this study. Investigators also concluded that these findings suggest a new paradigm for treatment of MMRd locally advanced rectal cancer, and continued recruitment and follow-up for the study is ongoing (NCT04165772).

Neoadjuvant PD-1 Blockade in Advanced MMRd Rectal Adenocarcinoma: Takeaways

Manish A. Shah, MD:
This trial has enrolled only 13 patients so far, but to have such clear efficacy is remarkable, and it could be practice changing. It would be good to get the results of several more patients and longer follow-up data, but patients are achieving a clinical CR, showing that PD-1 blockade is very effective in MMRd tumors in the preoperative setting. By comparison, the clinical CR with CT and radiation is approximately 40%, so with 13 patients, we would expect 5 or 6 patients to have a clinical or pathologic CR. What we saw in this study is better than that, but as I mentioned earlier, the sample size is small. Furthermore, data suggest that the more immunosuppressed a patient is and the more lines of CT they have received, the less effective PD-1 blockade is. By comparison, patients in this study were newly diagnosed, not previously treated, and without metastatic disease. We would expect that PD-1 blockade might be an incredibly active treatment in this population, and this is what the study is showing so far. This has the potential to be paradigm changing. For this population, you could treat with PD-1 blockade without further radiation or CT or surgery. But again, we need more data and a longer follow-up period. Most of these patients—if they have progression—will have local progression. We are not so much worried about metastatic disease as about local recurrence, and at 12 months it is early to report on progression. I think 2 years would be a better mark to have more confidence that these patients will not require surgery.

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