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To the Editor: Neoadjuvant immunotherapy for early-stage mismatch repair deficient (MMRd) malignancies has varying degrees of success across studies. This is highly relevant as investigators explore surgery-sparing approaches in patients who achieve clinical complete responses (cCR). For example, the NICHE-2 trial investigated the combination of 4 weeks of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) as neoadjuvant treatment in early stage MMRd colon cancer before surgical resection reached a pathological complete response rate (pCR) of 68%1. In another trial, neoadjuvant anti-PD-1 treatment administered for 6 months for localized MMRd rectal cancers achieved a 100% cCR rate2. While in MMRd locally advanced gastric cancer, a 3-month exposure to anti-PD-1 and anti-CTLA-4 followed by surgery led to a pCR rate of 59%3. The duration of immunotherapy may contribute to the differences in CR rates. We performed a systematic review aiming to investigate the association between the duration of neoadjuvant immunotherapy in localized MMRd tumors and CR rate (Supplements, Figures S1-2 and Table S1). The duration of neoadjuvant treatment of MMRd colorectal cancer (CRC) with anti PD-1 alone ranged from 1 to 7 months and resulted in CR rates ranging from 0 to 100% (Table S2). Given the broad range of anti-PD-1 treatment duration, we performed a probit model fitting analysis showing a positive association between treatment duration and CR rate (P<1E-10; goodness-of-fit P=0.08) in non-metastatic CRC (Figure 1, Table S3 and Figure S3).

nd resulted in CR rates ranging from 0 to 100% (Table S2). Given the broad range of anti-PD-1 treatment duration, we performed a probit model fitting analysis showing a positive association between treatment duration and CR rate (P<1E-10; goodness-of-fit P=0.08) in non-metastatic CRC (Figure 1, Table S3 and Figure S3). Studies of the more potent combinations of anti-PD-1 and anti-CTLA-4 in the neoadjuvant setting for MMRd CRC used treatment durations ≤1.5 months, likely to mitigate toxicity. While this combination resulted in CR rates ranging from 68% with 4 weeks of treatment to 80% with 6 weeks of treatment, it would be expected that a longer duration of therapy would lead to higher rates of complete tumor ablation (Figures S4-5). Longer duration of neoadjuvant immunotherapy for locally advanced cancers may increase the CR rate and open the door for organ-sparing strategies. Organ preservation after a cCR to neoadjuvant immunotherapy (alone or combined with chemotherapy) such as in MMRd rectal cancer2 or in bladder cancer4, seems safe and has excellent outcomes which were achieved with treatment durations ≥3 months. Optimizing the duration of neoadjuvant immunotherapy alone or in combination with cytotoxic/targeted therapy may lead to effective strategies to maximize the number of patients who benefit from non-surgical immunoablative approaches and may provide insights into the minimum duration of therapy in adjuvant and metastatic settings.