Why this matters
Checkpoint inhibition alone has limited activity in proficient mismatch repair rectal cancer, but combining immunotherapy with chemotherapy and radiotherapy may create a more favorable antitumor immune response.
TORCH-iTNT addresses a particularly interesting question: once PD-1 blockade and CAPOX are already part of total neoadjuvant therapy, does radiotherapy still add meaningful benefit?
The initial randomized results suggest that it does.
Adding short-course radiotherapy before immunochemotherapy increased the complete response rate substantially and led to more patients entering a watch-and-wait strategy.
But these are early phase II results from patients who completed treatment, and long-term disease control remains unknown.
Study design
TORCH-iTNT is a multicenter randomized phase II trial in patients with proficient mismatch repair locally advanced rectal cancer.
Eligible patients had:
- cT3-4 and/or node-positive disease
- M0 disease
- pMMR tumors
Patients were randomized to:
Group A
- 6 cycles of CAPOX
- toripalimab
- no upfront radiotherapy
Group B
- short-course radiotherapy, 25 Gy in 5 fractions
- followed by 6 cycles of CAPOX
- toripalimab
Patients achieving clinical complete response could choose a watch-and-wait strategy.
Patients without clinical complete response were recommended to undergo surgery.
In the non-radiotherapy arm, postoperative chemoradiotherapy could be given for positive circumferential resection margins.
The primary endpoint was complete response, defined as the combination of clinical complete response and pathological complete response.
Secondary endpoints included:
- organ preservation
- anorectal function
- toxicity
- survival outcomes
A total of 192 patients were enrolled.
At the current analysis, 148 had completed treatment:
- 70 without SCRT
- 78 with SCRT
Importantly, 96.6% had at least one high-risk feature such as low tumor location, cT4 disease, cN2 disease, MRF involvement, or EMVI.
Key results
Complete response substantially favored the addition of short-course radiotherapy.
Overall CR was:
- 37.1% without SCRT
- 61.5% with SCRT
This represents an absolute difference of approximately 24 percentage points.
The difference was driven by both clinical and pathological response.
Clinical complete response leading to watch-and-wait occurred in:
- 7 patients without SCRT
- 25 patients with SCRT
Among patients who underwent surgery, pathological complete response was:
- 32.8% without SCRT
- 44.2% with SCRT
The pathological response difference was smaller than the overall CR difference, suggesting that much of the organ-preservation signal came from the higher rate of clinical complete response.
Organ preservation
The watch-and-wait results are particularly relevant.
Twenty-five patients receiving SCRT followed by CAPOX and toripalimab achieved clinical complete response and entered watch-and-wait, compared with only 7 patients receiving immunochemotherapy without upfront radiotherapy.
This suggests that short-course RT may remain an important component of organ-preservation strategies even when highly active immunochemotherapy is used.
However, follow-up is currently too short to determine whether these clinical complete responses are durable or whether local regrowth rates differ between the groups.
Toxicity
Severe toxicity appeared broadly similar between treatment strategies.
The most common grade 3-4 adverse event was thrombocytopenia:
- 12.9% without SCRT
- 14.1% with SCRT
The current report therefore does not suggest a major increase in severe hematologic toxicity from adding short-course radiotherapy.
More complete toxicity and functional outcome data remain important, particularly because one of the motivations for omitting radiotherapy is to reduce long-term anorectal and pelvic functional impairment.
Interpretation
TORCH-iTNT asks a clinically important question that goes beyond whether immunotherapy works in pMMR rectal cancer.
It asks whether radiotherapy remains necessary when chemotherapy and PD-1 blockade are already combined.
The early answer appears to be yes, at least if complete response and organ preservation are the goals.
Adding 25 Gy in 5 fractions increased overall complete response from 37.1% to 61.5%.
The difference in pathological complete response alone was more modest, 32.8% vs 44.2%.
The larger separation in overall CR therefore appears partly driven by patients achieving clinical complete response and avoiding surgery.
That makes the result particularly relevant to watch-and-wait strategies.
But several important questions remain unanswered.
First, the current analysis is based on the 148 patients who completed treatment rather than the entire randomized cohort of 192 patients.
Second, complete response is not equivalent to durable organ preservation.
Patients managed with watch-and-wait require long-term follow-up for local regrowth, salvage surgery, distant metastasis, and survival.
Third, omission of radiotherapy may still have functional advantages that are not captured by response rate alone. The trial was specifically designed to evaluate anorectal function, and those results will be essential when judging the true tradeoff.
The current data therefore support radiotherapy as an important contributor to response, but do not yet establish that the higher CR rate translates into superior long-term patient outcomes.
Limitations
The current analysis is interim.
Only 148 of 192 enrolled patients had completed treatment and were included in the reported efficacy analysis.
Long-term disease-free survival, overall survival, local regrowth, and organ-preservation durability remain immature.
The current report also does not yet provide mature comparative anorectal functional outcomes, which are central to the rationale for potentially omitting pelvic radiotherapy.
The pathological response analysis includes only patients who underwent surgery and therefore does not represent the entire randomized population.
Finally, this is a phase II trial and requires longer follow-up before treatment de-intensification or escalation strategies can be defined.