Abstract
BACKGROUND
Neoadjuvant chemotherapy and radiation [this means treating a tumor with chemo and radiation with the purpose of shrinking it in preparation for surgery. Makes it easier to remove and less intestine has to be wasted] followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair [uh oh, this is a SUBSET of rectal cancer? What’s the percentage of rectal cancers that have this particular defect, you ask? FIVE to TEN PERCENT. Boooo. On the other hand, the ones that do have this defect are resistant to standard therapy, so for these people it’s a good deal. But this study does not pertain to 90+% of people with colon cancer]. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, [in other words, in patients in whom cancer has spread to a distant site (stage IV or metastatic cancer), blockage of this PD-1 receptor system had some effectiveness]it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer. [sure! Try everything! if it worked in Stage IV disease, maybe it’ll work here, too. The cool thing is how they did this study, and with what new agent. See below]
METHODS
We initiated a prospective [watching something go forward, rather than looking at charts in the past (aka retrospective study)] phase 2 [phase 2 studies are small, looking for effectiveness before proceeding to much larger phase 3 trials]study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody [basically a single antibody, made in the lab, produced by hybrid cells that can be “trained” to make the antibodies you want], was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma [cancer that is bigger than stage I but has not spread to a distant site. Therefore the term “locally advanced.”]. This treatment was to be followed by standard chemoradiotherapy and surgery [the plan was to give this antibody, then move on to chemo, radiation and surgery and see how they did. There’s a twist, though, read on.]. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery [wow! If, on the odd chance that the antibody induced a complete response (remission, cancer-free, whatever you want to call it), the patient WOULD NOT GET CHEMO/RADIATION/SURGERY…they’d just watch them and see!]. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. [basically they were looking for sustained periods where the cancer could not be detected clinically or pathologically]
RESULTS
A total of 12 patients [UH OH. twelve patients…TWELVE PATIENTS?!!?? This is a pretty small phase II trial (the Pfizer vaccine had 3000 in its phase II trial if I remember correctly (I could take 2 seconds to look it up but I’m lazy and it doesn’t really matter for the purposes of this discussion)] have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response [ok, that is a pretty outstanding result. we almost never get 100% of anything in medicine. The odds that this is chance, however, are not zero, thanks to the vanishingly small sample size. But still!], with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. [so they did a bunch of tests and there was o evidence of tumor. That’s all you really need to know on that sentence.] At the time of this report, no patients had received chemoradiotherapy or undergone surgery[this is the fun twist. The chemotherapists, radiation oncologists and surgeons were all standing by to proceed with these patients…and the call never came. Not one of them had chemo, radiation, or surgery.], and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. [so stage IV events require hospitalization often and termination of the study. Stage III is below that, think bronchospasm/asthma (Stage 3) vs anaphylaxis (stage 4)]
CONCLUSIONS
Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response.
