We have a vested interest for patients with rectal cancer to try and obviously cure their cancer but also try to cure their cancer with the least morbid treatments. Right now the standard of care across the world for treating rectal cancer in the early stages, meaning stage 2, stage 3, sometimes even stage 1, is to give people chemotherapy, radiation and often surgery. The surgery can be very morbid – for most patients it involves removing the entire rectum and they need a lifelong ostomy bag. So this is a life-changing surgery. So all of us around the world are trying to find ways of getting rid of the tumour and avoiding surgery while we’re doing that.

So those were the two big missions. Our study looked at patients that have something called HER2 amplification in the rectal cancer, meaning their cancer overexpresses the HER2 protein on the surface. In patients with advanced metastatic stage 4 disease HER2 therapies against the tumour have been very successful in patients that have HER2 amplification, so it was a very natural conclusion to try and bring this into the early-stage setting to help cure people, again without surgery.

We included HER2 treatments, there were two different drugs – trastuzumab and tucatinib – alongside chemotherapy in the early-stage setting for patients with rectal cancer. All the patients were also KRAS wildtype, meaning they didn’t have the KRAS mutation. We know this is important because in the metastatic setting KRAS mutations confer resistance to HER2 treatments.

The way we set up our trial is we included a six-week period, which is two full cycles, of HER2 therapy alone, which was interesting. Then we have an exploratory assessment after that period to see if maybe patients don’t need chemotherapy either, maybe we can just do HER2 therapy in the neoadjuvant setting. So we tried that initial six-week period and then after that six-week period we added an additional 15 weeks, a little over four months, of trastuzumab, tucatinib and standard of care chemotherapy to the patients and this was their first treatment. So the patients hadn’t gotten radiation or any other treatment for their locally advanced rectal cancer.

So that’s how we set up the trial and then after that final 15 weeks, so in total a little over five months of treatment, we have a final assessment where we give an endoscopy, a biopsy, a CAT scan, an MRI and we see whether the cancer was still present or not. If the cancer was still present then the patient went down the normal treatment route which was chemoradiation or surgery, depending on the multidisciplinary committee. But if the tumour was gone, if it had completely resolved, what we call a complete clinical response, on all of those assessments then we gave the option for watching these patients non-operatively. So basically doing very close surveillance without doing surgery or radiation. The main outcome of the study was the responses of the tumours after this treatment, so how many had shrunk, and then also the complete response rate at that week 21 or just over five months of treatment.

How was HER2 amplification identified?

We basically used the standard of care that we use in gastric cancer and it’s very similar to the standard of care for breast cancer. We instituted an institution-wide screening, every patient that had locally advanced rectal cancer was screened with immunohistochemistry. If the patient had 3+ staining on their immunohistochemistry for HER2 they were eligible for the study, or if the patient had 2+ staining of HER2 plus a positive FISH they were eligible. All of the patients were mismatch repair proficient and all of them were RAS wildtype. So we were able to implement this screening process which was pretty feasible, I think that’s another message, maybe, to the community. We don’t typically screen patients for HER2 in the early-stage setting but screening for both HER2 and RAS was very feasible, it took about a week, a little longer than a week. No patient, again, missed a window of opportunity with this overall design for anything, it didn’t harm them to do this.

What were the key findings?

We did an institution-wide screening so this is pretty rare. HER2 amplification was only about 2.4% of patients with locally advanced rectal cancer out of almost 500 people that we screened. So it was a rare instance. We had ten patients on the study that were presenting. These are interim results, so we are still accruing patients and the study is still ongoing but we achieved the stage 1 endpoint so that’s why we wanted to present today at AACR.

Out of those ten patients, nine of them had completed the first six weeks of HER2-only treatment and seven of those patients had a dramatic response. So the response rate to just HER2 therapy was very high – almost every patient had a response, two patients just had stable disease so no patient progressed on treatment. Then, at the final endpoint, eight patients have so far reached that point out of the ten, and half of them, or 50%, so four patients, 50%, had a complete clinical response. So that was the endpoint.

Based on our Fleming two-stage design we had to have at least four patients to advance to the second stage of the study. So we achieved that endpoint, it’s still ongoing, low numbers of patients but half of them did have a complete clinical response.

What adverse events did you see?

The treatment was very safe so whenever we’re thinking about neoadjuvant treatments we want to make sure that patients aren’t progressing so we’re missing a window of opportunity to do a surgery, to do radiation. That didn’t happen for any patient, it was very safe and it only benefitted people. The other thing is that the adverse events that we saw were relatively minor and reversible. We saw some transient rise in liver enzymes that just came down over time and we saw some diarrhoea, which is a known side effect of HER2 treatments , which was very manageable with Imodium.

Could these results support a biomarker-driven non-surgical approach for some patients?

I think so and I think in a bigger context we’ve seen in colorectal cancer, as with other diseases, moving the biomarker-directed therapy earlier in the line of therapy for metastatic disease. I think this is really emphasising that these HER2-targeting treatments can be very effective as part of neoadjuvant chemotherapy in the early-stage setting too.

I will tell you, and we’re going to talk about this at the conference, there were recurrences, local recurrences, in some of the patients that had a complete clinical response. So none of the patients required surgery, so that’s very exciting. 63% of the patients overall, or 5 out of 8 in the study, have not required surgery after a follow-up of about 30 months, so about 2½ years, which is very exciting. Again, these patients don’t tend to do very well. HER2 amplified tumours in the metastatic setting have more brain mets, they have more bone mets, they have more metastatic sites. We did an observational study that we’re going to include in the presentation in the early-stage setting as well. It’s less than 30% of patients that have organ preservation with TNT, which is chemotherapy and chemoradiation. So most of these patients are still requiring morbid surgery. So the fact that we have 63% of patients avoiding surgery in our study is really remarkable and I think that’s assisted by these neoadjuvant-directed treatments against a biomarker, HER2 therapy, which were very effective.

So it’s important to stress these are very effective drugs, they make these bulky, big tumours… again, 70% of our patients had lymph node positive disease on clinical staging, so these are aggressive tumours. Again, 63% of them didn’t require surgery, there was marked shrinkage, half of them had a complete clinical response. All of the recurrences that we saw were salvageable without major surgery, one patient got radiation, one patient got an endoscopic resection, basically it was a polyp and they had an endoscopic resection.

So I think it’s very much proving the point that targeted treatments can do well in the early-stage setting for rectal cancer.

The last thing I want to say, just on the recurrences standpoint, because I think there are going to be questions about this at AACR, is that all of the recurrent tumours were still HER2 positive. So it really makes us wonder, maybe, even though we treated patients for five months, which is a pretty long time, maybe patients need more treatment because their tumours at the end of the day were still HER2 positive, they still might have been sensitive to that treatment. So in breast cancer we treat people for sometimes a year or more of HER2 therapy in the early-stage setting, maybe a similar paradigm is needed for targeted treatments in rectal cancer. Maybe we need to treat people longer than we typically do with just chemotherapy.