Evolving Testing and Treatment Strategies in Metastatic Colorectal Cancer - Episode 9

HER2+ Metastatic Colorectal Cancer: Clinical Trial Data With Tucatinib

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A panel of oncologists shares comprehensive insight to clinical trial data with tucatinib in patients with HER2+ metastatic colorectal cancer.

Transcript:

John L. Marshall, MD: So Cathy, talk us through some of [the things in therapy] that are going on, and the approach. How we should think about HER2+ colon [cancer if] we open our report up and there it is, HER2+?

Cathy Eng, MD, FACP: HER2, it’s very rare in colorectal cancer. I think we mentioned it a little bit earlier, it’s about 4% of our patient population and we had some earlier data. But most recently the data that Dr Saab has been involved in from Jonathan H. Strickler [MD] demonstrate that tucatinib in combination with Herceptin, trastuzumab, is an appropriate approach for our patient population who may have been previously treated if they’re HER2+. And it was specifically [used], as mentioned earlier by Stacey, in our 2+ or FISH+ [fluorescence in situ hybridization], or 3+ by IHC [immunohistochemistry] patient population.

But there is the antibody-drug conjugate deruxtecan, which a lot of people are interested in, but it does have some potential associated toxicities. I think we found out yesterday the dosing should be 5.4 mg/kg. So I think we’ve figured that out; those are our 2 options. I would like to point out that the original DESTINY trial though is a unique trial because it does allow patients who have received prior HER2-based therapy. That’s really important to keep in mind.

John L. Marshall, MD: A lot to unpack here. Thank you very much for that. So Tani, another investigator-initiated study, MOUNTAINEER, a sort of dream on a rare patient population, a culture that’s not routinely testing for these patients, so it’s not like you just happened to have it in your chart. So it really took a lot of work. You’re very involved in making that study happen and [giving] access to those around the country and world to participate in that. Walk us through the study and how important this drug development is today.

Tanios Bekaii-Sabb, MD, FACP: This was an interesting study brainchild of John Strickler through our accrual research consortium. We started this as an investigator-initiated trial and I was the senior lead [investigator] on that study. Actually, the IND [investigational new drug application] was held through accrual through Mayo Clinic. It really started as an 8-institution study with 2 accruing sites, Mayo Clinic in Arizona and Duke [University], and then it started expanding. And as the signals looked more and more promising—

John L. Marshall, MD: Open label phase 2?

Tanios Bekaii-Sabb, MD, FACP: Open-label phase 2, 45 patients was the goal. And as the signals were promising then the company got interested in taking over the IND, which remained mostly through accrual but also became a global study with a registration intent, with a randomized question of what is the contribution of trastuzumab to tucatinib? So there was an arm with tucatinib alone. It wasn’t powered to directly compare the two, but just to get an idea with a crossover design, what happens when we add back trastuzumab to patients who essentially do not have a response to tucatinib.

The study ended up meeting its primary end point. It was approved by the FDA January 19, 2023—the first approval in the United States, which is fantastic. And again, this is the power of academic and industry related collaborations in moving the field forward in a rare subset of colorectal cancer.

John L. Marshall, MD: I want to do a quick summary of what you just said. Dung Le [MD] out of [Johns Hopkins], the MSI [microsatellite instability]-high approval is the first agnostic ever.

Tanios Bekaii-Sabb, MD, FACP: Absolutely.

John L. Marshall, MD: She was convinced this was the right thing to do and it’s actually [Johns] Hopkins philanthropy that started that. Then you get Scott Kopetz [MD, PHD] in Houston who says, BRAF, we’ve got to be able to do this. And now we have John and [your team] saying we can do this.

Tanios Bekaii-Sabb, MD, FACP: We can do HER2.

John L. Marshall, MD: I just want to echo that: Don’t give up out there, academic doctors.

Tanios Bekaii-Sabb, MD, FACP: No, the default is always [to think] this is a rare target. I’m not sure it’sworth it. If we want to go historically, the first study that was published by [INAUDIBLE] with irinotecan and trastuzumab had an interesting response rate. In the early 2000s, it was held because HER2 amplification was not considered as a viable target because it only was found in 7% of the patients. Can you imagine?

John L. Marshall, MD: Seven?

Tanios Bekaii-Sabb, MD, FACP: Seven percent. Today we’re talking about 1% and 2%, and even less than that.

John L. Marshall, MD: Remind our audience of the benefit rate. So it was a response rate and the duration of response, I think.

Tanios Bekaii-Sabb, MD, FACP: So the duration of response is remarkable. The response rate is very solid, 38.1%. The duration of response is 12.4 months in the hole. However…if you go and look at the centrally confirmed plus [patients], the duration of responses goes to 16 months [for] those who actually express, whether 3+ or 2+ ISH. In fact we haven’t done or isolated the 3+ alone, but I suspect that that’s going to continue to expand. Imagine this: We have [about 5] patients now, including a patient of mine, and couple of patients of John’s, a patient of [INAUDIBLE] that have been 3, 4, 5+ years out just on tucatinib and trastuzumab doing great in CR [complete remission]. And the toxicities were very reasonable, [though we] never want to undermine any level of toxicity.

John L. Marshall, MD: Let’s go there. I was new to this drug. I’d given it before, I now have a few patients on it. I was impressed by, say, diarrhea. I went down the hall to our breast cancer colleagues and said, what do I do? What’s your take on this?

Aparna R. Parikh, MD: So we were also a subsite in MOUNTAINEER. I think aggressive diarrhea management and then dose modifications really manageable. So kind of hold, modify, get the diarrhea under control, and then just educate people that they’re not going to overdose on Imodium.

John L. Marshall, MD: GI [gastrointestinal] oncologists have to remember, you still need heart tests and things like that.

Aparna R. Parikh, MD: Yes, of course.

John L. Marshall, MD: It’s not on our radar as much as it is [for other cancers], but we have to do all of those things. So it is that sort of same classic thing that you’re doing down in your breast cancer patients [with] these doublets; it’s basically the same.

Aparna R. Parikh, MD: Yes, and I think the other just thing to note about tucatinib is the CNS [central nervous system] penetration, too, which is a little bit different, at least from the larger antibodies.

John L. Marshall, MD: And we’re seeing more of that, at least I am.

Aparna R. Parikh, MD: I am, too.

John L. Marshall, MD: Younger patients with brain metastases.

Aparna R. Parikh, MD: I think there are a couple of patterns that we’ve noticed. I think some are just the patients who live a really long time with metastatic CRC who ultimately develop brain metastases. But there’s been some observational data … that suggest that maybe there’s a little bit of a proclivity for HER2 in the brain, too. So it makes you feel a little bit good.

John L. Marshall, MD: What do you think about the design of his study, MOUNTAINEER-03? Do you like it [for] the front lines?[Tanios is] sitting right there, so be careful.

Aparna R. Parikh, MD: I think it’s a great study. I think the chemotherapy combination makes a lot of sense. It might have been interesting to see a chemotherapy-free option in that study, the way they’ve done with BRAF. I had mentioned that along the line.

John L. Marshall, MD: You only have 2% of the patients. You have to have realistic trade-offs.

Tanios Bekaii-Sabb, MD, FACP: There was some reluctance.

John L. Marshall, MD: You will get some maintenance. You’ll end up on a maintenance [therapy].

Aparna R. Parikh, MD: That’s true.

Tanios Bekaii-Sabb, MD, FACP: I actually agree. I think you probably don’t need chemotherapy in this subgroup of patients. In fact, there are hints from smaller subsets, here and there, that the HER2 amplified tumors in colorectal cancer may not be as aggressive, but they don’t seem to do as well with chemotherapy, or they may not need chemotherapy. So I agree, but it made a lot of folks uncomfortable. It would have been nice to have a separate [study]. It’s not feasible, unfortunately, with such a rare target, but I totally agree. I think the best strategy ultimately would be, if the study’s positive, to do chemotherapy for 6 cycles, maybe 8 cycles, and then just go with the biologics. Minimize chemotherapy or the role of chemotherapy. But the study, as designed, did include chemotherapy.

John L. Marshall, MD: I think the approval is after oxaliplatin, after irinotecan, right?

Aparna R. Parikh, MD: Or intolerance.

John L. Marshall, MD: RASwild-type, or BRAF wild-type.

Tanios Bekaii-Sabb, MD, FACP: No BRAF was not.

John L. Marshall, MD: No BRAF. Just RAS wild-type, andMSS [microsatellite stable] patients.

Tanios Bekaii-Sabb, MD, FACP: Yes, they also had if they were MSI high. Again, it’s a rare occurrence. Of course, you have to see IO, but you can actually exclude EGFR inhibitors here.

John L. Marshall, MD: Stacey, let me come to you on that. This is a second-line kind of feeling thing to me. I’ve got 38% response rate, and a year average duration response. I haven’t given irinotecan yet or something like that. Can you give us a little thought about where you would be [for] second line if you haven’t met the official criteria?

Stacey Cohen, MD: You know, as Aparna mentioned, sometimes we can use intolerance as a way to sort of flex in this situation. Had a patient been treated with FOLFIRINOX [leucovorin calcium, fluorouracil, irinotecan, oxaliplatin] in the first line, then unfortunately I amrunning out of therapies earlier than I would like. You could end up in a second-line patient and be on label for that. I think we’re really finding that it’s hard to get these trials done, it’s hard to accrue enough patients, but they’re definitely out there. So maybe we don’t know yet if it’s a first-line option, and I don’t think that we should outside a trial just yet, but I think second line and beyond is really where we are thinking about this therapy.

John L. Marshall, MD: That seems right, seems where it fits. Cathy, would you sort of go with that same sort of strategy of [putting] in HER2 targeting?

Cathy Eng, MD, FACP: I could completely agree with Stacey, definitely.

John L. Marshall, MD: Coming into that second line.

Transcript edited for clarity.