Tucatinib/Trastuzumab Approval Highlights Expansion of Tailored Therapies in HER2+ CRC

John L. Hays, MD, PhD

The FDA approval of tucatinib (Tukysa) plus trastuzumab (Herceptin) for patients with HER2-positive metastatic colorectal cancer (CRC) represents another tailored treatment option for a subset of patients who, until recently, had few avenues following standard-of-care chemotherapy, according to John L. Hays, MD, PhD.

In January 2023, the regulatory agency granted accelerated approval to tucatinib in combination with trastuzumab for adult patients with RAS wild-type, HER2-positive unresectable or metastatic CRC that has progressed after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.¹

The decision was supported by data from the phase 2 MOUNTAINEER trial (NCT03043313), which showed that patients treated with the combination (n = 84) achieved an overall response rate of 38% (95% CI, 28%-49%), including 3.6% of patients who experienced a complete response. The median duration of response was 12.4 months (95% CI, 8.5-20.5).

“It’s exciting that we finally have an approval for something in this cohort of patients [with HER2-positive CRC]. We have had number of phase 2 trials that have shown benefit for small molecules, antibody-drug conjugates [ADCs], and antibodies targeting HER2, but nothing had been approved in that space,” said Hays, who chaired an OncLive^® State of the Science Summit^™ on gastrointestinal cancers. “This provides a strong backing for using this type of regimen in patients who have this type of HER2 overexpression.”

In an interview with OncLive, Hays discussed the continued importance of tailoring therapies for patients with CRC who express HER2 or have other actionable targets, the need to develop optimal sequences for local and systemic therapy in CRC, the role of clinical trials in the treatment of patients with CRC and other malignancies, and key updates in hepatocellular carcinoma (HCC) and pancreatic cancer. Hays is an assistant professor in the Department of Internal Medicine at The Ohio State University and a member of the Translational Therapeutics Program at The Ohio State University Comprehensive Cancer Center (OSUCCC)­­–James in Columbus.

OncLive: What has the emergence of different individualized treatment approaches for subsets of patients with CRC, such as those with HER2-positive disease, meant for the treatment landscape?

Hays: The goal of my talk was to encompass [not only] HER2, but a number of other targeted therapies in CRC. What I wanted to get across was that 15 years ago, we used a lot of FOLFOX, FOLFIRI, and bevacizumab [Avastin], and we were just starting to get into EGFR inhibitors. Then we were in stasis for about 10 years. However, over the past 5 to 8 years, we have had an explosion of understanding the molecular aspects of colon cancer and how we can target some of those things to achieve good results in populations where we [previously] may not have had that opportunity.

Many of these [alterations] are not expressed in a lot of patients with CRC. For example, we have known about [HER2] for a long time with[in] gastric cancer and breast cancer, but in about the 5% of patients with colon cancer who overexpress HER2, they can respond well to various types of inhibition of that protein. This is opening a new world in colon cancer where we can, instead of just talking about FOLFOX and FOLFIRI, [ask] how we can add [other agents] to them, and make [treatment] better and more targeted toward our patients.

I do not mean to say that FOLFOX and FOLFIRI are bad. They do wonderfully. One of the trials that I presented to get that point across was the [phase 3] TRIPLETE study [NCT03231722], [which showed that] mFOLFOX and panitumumab [Vectibix] had a [76%] response rate in the up-front setting, which is quite remarkable.²

What is the importance of testing for HER2 and targetable markers in metastatic CRC?

One of the exciting things is that we know that HER2 is expressed in a small number of patients with colon cancer. In patients that had been fairly heavily pretreated with a number of different regimens—generally they’ve gone through all of the 5-fluorouracil [5-FU]–based regimens—we still see respectable response rates for targeting HER2 with various combinations of small-molecule inhibitors, antibodies, or ADCs.

The MOUNTAINEER trial led to the approval of the combination of tucatinib plus trastuzumab. If you look at the data, there was a [38%] response rate in patients who were heavily pretreated with metastatic CRC, and that is almost unheard of. I [previously] had patients [where] once we were past their 5-FU–based regimens, there was not a lot that we could do. Now, all of a sudden, I have multiple treatment options that we can bring them that seem quite helpful.

The other side is, th[ese developments are] not just with HER2. [You could] look at the data that have come out with RAF inhibition [and] the [phase 3] BEACON CRC trial [NCT02928224] in patients who had 1 or more line of therapy. Patients with BRAF mutations tend to have a much more aggressive tumor and [do] not respond very well to chemotherapy. All of a sudden, [patients on the trial] had quite good response rates to targeted therapy for their BRAF mutations [with cetuximab (Erbitux) plus encorafenib (Braftovi)]. We are all excited to see what the frontline data are going to be in the ongoing [phase 3 BREAKWATER trial (NCT04607421)] for this combination with or without 5-FU–based regimens.

How else has the treatment paradigm evolved for patients with metastatic CRC that progresses following standard-of-care chemotherapy?

We used to have in our minds that we gave FOLFOX, FOLFOXIRI, or 5-FU–based regimens, and then there was not much left to do. As it turns out, we have a lot of new drugs that have been approved, and we have a lot of things in the pipeline that look very promising for the near future. That is exciting for all of us. I have had plenty of patients with colon cancer [where] we reached the end of the available treatment options, and the patients were still healthy and doing well. I wanted to be able to offer them something, but we did not have anything. Now, we have new things being looked at.

I [also] talked about the [phase 3] FRESCO-2 trial [NCT04322539], which is looking at another way of [using] VEGF inhibition [with fruquintinib (HMPL-013)]. We also talked about KRAS inhibitors, and although most of the KRAS mutations we see in colon cancer may not make [patients] eligible for the current batch of inhibitors, it still is a subset of the population that can have remarkably good responses to these targeted agents [designed] for mutations that we find in colon cancer. Getting the first [KRAS inhibitor approved] will get our toe in the door. The hope is that there are more trials and more drugs in the pipeline for targeting other KRAS mutations that may be more commonly found in colon cancer. All these data give us great hope for where we are going over the next 5 to 10 years in colon cancer that we did not have 10 years ago.

What other unmet needs still need to be addressed within CRC?

One of the ongoing issues is going to be the integration of surgery, radiation, and systemic therapy. We have very strong data in the up-front setting for treating oligometastatic disease and the idea of giving chemotherapy or some systemic therapy around that. However, many practicing oncologists would say that throughout the spectrum of treating someone with CRC, there is going to be the usage of targeted therapies, systemic therapies, local therapy, surgery, and radiation, and even pseudo-local therapies with things like hepatic arterial infusion pumps or Yttrium-90 treatment for liver disease. Trying to understand the overall spectrum of where these [approaches] fit is going to be our next great question.

It is a great problem to have, which we have not had in CRC before. We are starting to have enough active therapies [where] we get choices, and we do not know the right answer sometimes. That is an exciting part that we now have enough active drugs that we have that problem, and it is not something we have had to deal with. [However], we can do much better and we should do much better.

[Another topic I discussed was] immune therapy, [which] we were all buoyed by. Mismatch repair–deficient [dMMR] patients have remarkable responses to immune checkpoint inhibitors. The recent [phase 2] trial [NCT04165772] in the frontline setting for patients with dMMR locally advanced rectal cancer showing a complete response in all patients who were treated was mind boggling. However, that does not work in most patients who are not dMMR. Therefore, trying to figure out how we can harness the immune system in this other large population of patients is another ongoing question. Whether that is with cellular therapies or with targeted therapies combined with immune therapies is something we must look into closely.

Anne M. Noonan, MBBCh, of OSUCCC–James, discussed managing HCC. What have advances in this space meant for treatment options for patients with HCC?

Even more than CRC, if you looked at [treatment options for] HCC 10 years ago, there was nothing that was active. We had sorafenib [Nexavar], and while that showed some clinical benefit, it was fairly minimal in most patients, and it was limited to patients who had good liver function. What we are seeing now, in the past 5 years, the number of agents that have been approved in HCC is just remarkable. With targeted therapy, immunotherapy, and the combinations therein, this is a whole new world that we are dealing with.

Not only [are new treatments] helping people live a lot longer, but they are opening treatment to people who [previously] never would have been eligible for treatment. That was always one of the big questions with HCC. We had treatment options for people who are otherwise in perfect health, but many of our patients with HCC are not in perfect health to start with. We needed [treatments] that we could give to people whose liver was not functioning perfectly. Now, we are starting to have those options. Even in my time as a practicing oncologist, that has gone from nothing to a whole lot of things, which is incredible.

When I was in training, my mentor used to tell me that she was glad she was not [training to be] an oncologist today. When she was training, it was easy to learn 1 or 2 drugs for every disease. Now there are 10 to 15 different treatments for every disease, which is a lot better for the patients, but harder to keep up with sometimes.

Pannaga G. Malalur, MBBS, of OSUCCC–James, discussed updates in pancreatic cancer from the 2023 Gastrointestinal Cancers Symposium. What are some of the implications from results of the phase 3 NAPOLI 3 trial (NCT04083235) in patients with metastatic pancreatic ductal adenocarcinoma?

Ten years ago in pancreatic cancer, we had nothing that was terribly effective. Now, we have a couple of regimens that we are all excited about. We are still trying to figure out how to use them perfectly, how to sequence them in every patient, and which patient population should be treated with which [regimen]. The NAPOLI 3 trial offered a different look at FOLFIRINOX, using a different form of irinotecan [liposome injection (Onivyde)]. It was the first trial comparing a FOLFIRINOX-like regimen [of] NALIRIFOX [irinotecan liposome injection, 5-FU/leucovorin, and oxaliplatin] vs nab-paclitaxel [Abraxane] plus gemcitabine, and [NALIRIFOX] outperformed nab-paclitaxel plus gemcitabine.

This is something that we have not had data historically to say which regimen might be better. That was the first insight that there may be a slight improvement for using a 5-FU–based regimen compared with the gemcitabine-based regimens, although it was not a huge [improvement]. There are [differing] toxicity profiles between the 2 [regimens], and it is something we always worry about when using the 3-drug regimens, as they do tend to be a little bit more toxic than the 2-drug regimens. That being said, having something else in our arsenal, in a disease that is otherwise horrific to deal with, is always going to be important.

Considering the advances made in CRC and other malignancies, how do you approach clinical trial enrollment as an option for your patients?

My biggest push is that clinical trials in general are our single greatest resource for almost all patients with cancer. While we have very good standard-of-care regimens and we should use those whenever we need to, we should always be looking to offer our patients the next, best, greatest things that are available. The way you do that is with clinical trials, and we will never learn what the next best thing is if we cannot put patients on clinical trials.

I am always an advocate [for trials] at every decision point in every patient I see. Are there trials available that we can talk about? That does not mean we try to push every single patient onto a trial, but we try to give them the option that if they want to do that, [they can if the trial] is there. My push is for everybody and for all my oncology colleagues to please think of clinical trials for your patients at any given time. It is the way we move our field forward.

References

1. Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. January 19, 2023. Accessed April 11, 2023. https://investor.seagen.com/press-releases/news-details/
2. Rossini D, Antoniotti C, Lonardi S, et al. Upfront modified fluorouracil, leucovorin, oxaliplatin, and irinotecan plus panitumumab versus fluorouracil, leucovorin, and oxaliplatin plus panitumumab for patients with RAS/BRAF wild-type metastatic colorectal cancer: the phase III TRIPLETE study by GONO. J Clin Oncol. 2022;40(25):2878-2888. doi:10.1200/JCO.22.00839