Actionability of HER2 Target for GI Cancers Expands With Newer Agents

Axel Grothey, MD

HER2 has emerged as targetable alteration for various gastrointestinal (GI) cancers, leading to numerous treatment options in both the first and later-line setting for these patients.

Historically, trastuzumab (Herceptin) has shown efficacy against the HER2 target especially in breast cancer. However, newer agents are also showing efficacy against HER2 alterations and overexpression in GI cancers. For example, trastuzumab deruxtecan (T-DXd; Enhertu) was recently approved for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal adenocarcinoma who have previously received trastuzumab-based therapy,1 and the antibody-drug conjugate (ADC) is already making its way into clinical guidelines and practice.

Other potential agents against HER2-driven GI tumors showed efficacy in presentations at the recent American Society of Clinical Oncology 2021 Gastrointestinal Cancers Symposium (ASCO GI).

Axel Grothey, MD, director of GI cancer research at West Cancer Center and Research Institute, discusses in an interview with Targeted Oncology how HER2 has become an actionable target for GI cancers and potential HER2-targeted treatments in the field as well as other interesting studies from the the role trastuzumab plays in the GI cancer clinical space and how HER2 has become a more actionable target for this patient group.

TARGETED ONCOLOGY: In your opinion, has HER2 become an actionable target for GI cancers? And could you discuss the introduction or integration of HER2-targeted therapies in the GI cancer space in general?

GROTHEY: HER2 is definitely a targetable alteration in various GI malignancies. In 2010, we had data from ToGA (NCT01041404), a phase 3 study adding trastuzumab, a HER2 targeted antibody, to standard platinum-based chemotherapy with survival benefit. And the interesting thing was that, in contrast to breast cancer, the development of HER2-targeted therapies, at least in gastric cancers, was stalled for some time. There were no second-line trials that really showed survival benefit and it's not for lack of trying. So, trastuzumab has been the only agent that really worked in gastric cancer in the first-line setting. And we didn't do anything afterwards targeting HER2, and now we have data from T-DXd, which is this ADC that can actually provide benefit in patients who even had prior trastuzumab therapy for gastric cancer. Then, in other cancers, we have seen data in colon cancer from single-arm phase 2 studies initially come from Italy: combination therapy with trastuzumab and lapatinib (Tykerb), [in the] HERACLES study. Then [there was] the My Pathway study (NCT02091141), evaluating trastuzumab and pertuzumab (Perjeta) in heavily pretreated colorectal cancer (CRC) with HER2 expression. And trastuzumab and tucatinib (Tukysa), which is another HER2 kinase inhibitor. And more recently, again with T-DXd in the so-called DESTINY-CRC01 study (NCT03384940), which showed significant activity, even in patients who already had trastuzumab--similar story as in gastric cancer. And there are HER2 overexpressors even in gallbladder cancer and other cancers, so maybe we need to check for HER2 to really identify this targetable alteration.

TARGETED ONCOLOGY: You mentioned T-DXd, it was just approved in gastric cancer. What would you say are some of the clinical implications of that approval? And how is it being integrated into clinical practice?

GROTHEY: I think we're all very excited about T-DXd because we see the efficacy. Even in pretreated patients, we see the efficacy related to breast cancer, where it has been approved—actually for quite some time—gastric cancer, and also CRC. The main issue is that we can offer patients who have progressed on trastuzumab-based therapy in gastric cancer and colon cancer, a valid treatment option. Actually, they made it into the NCCN [National Comprehensive Cancer Network] guidelines already quite early. So, this is an active agent that combines an antibody target and linked chemotherapy drugs. It's kind of targeted chemotherapy, which makes it so exciting.

TARGETED ONCOLOGY: What are some of those questions that remain with this agent? And are there ongoing trials or anything in the pipeline with that agent that look promising?

GROTHEY: So, of course, when you have a drug that has activity in the later-line setting you want to move it into earlier-line settings. And the issue here is this is not just an antibody; this is an antibody plus chemotherapy. So, the question is how combinable is it with additional chemotherapy? How combinable is it with immunotherapy? There are studies that are ongoing right now, looking at the combination of T-DXd with topoisomerase inhibitors, chemotherapy, perhaps combined with a fluoropyrimidine, which is one of the standards of care in various GI malignancies, and, of course, immunotherapies everywhere. Targeted therapies combined with VEGF inhibitors, for instance. Bevacizumab (Avastin) in colon cancer. All these trials and studies need to be worked through. Hopefully we'll see the emergence of data very soon.

The critical issue here is, and I think that's something we need to keep in mind before we move it into earlier lines of therapy, is getting a handle on one of the most important [adverse] effects (AEs) of this agent, which is interstitial lung disease, which is something we've known for quite some time, particularly in CRC studies. In the DESTINY study, there were 2 patients who actually had grade 5 toxicity so they died of interstitial lung disease, or pneumonitis. That's a COVID-like syndrome. So, we're all quite aware of this. It's interstitial with lung parenchyma. And we're still trying to figure out who are these patients, what's the onset? How do we monitor these patients etc. in a later-line setting when we're really backed against the wall, and we take more AEs potentially into account to make a difference. In earlier-line settings and potentially adjuvant settings where we have much healthier patients, we really do not want to inflict harm. So, we need to get a handle on that.

TARGETED ONCOLOGY: At this year's ASCO GI, we saw some interesting data with different agents, one of them being patritumab deruxtecan, which targets HER3 instead of HER2.2 What sort of potential does that agent have? Should it continue to move on in the pipeline?

GROTHEY: Patritumab deruxtecan is kind of a similar idea to T-DXd, but targeting HER3. And HER3 is interesting because it's over expressed in the majority of patients with colon cancers. We have limited data in other diseases. But in colon cancer, CRC cells over express HER3 quite commonly. So if this actually works using HER3 as a target for drug delivery, it could apply to a lot more patients than, for instance T-DXd, because HER3 is only overexpressed in a fraction of patients with CRC and a larger percentage, of course, [of patients] with gastric or gastroesophageal cancer. So that has potential; we need to see whether this drug is efficacious. It should be because the mechanism of action is really the targeted delivery of chemotherapy. And if we have a target, and the drug is safe and we can deliver enough of the cytotoxic agent into the tumor cells specifically, it should work, but studies are ongoing. We just finished this kind of a lead-in study of these HER3 ADCs. We'll probably have internal data by mid-2021. And then hopefully, the drug will be moved forward.

TARGETED ONCOLOGY: And with that agent, are we seeing similar rates of interstitial lung disease? Or is that something that maybe looks like it was avoided?

GROTHEY: Unfortunately, it's too early to tell. We've treated 37 patients right now with colon cancer with a target dose. We are still doing a toxicity analysis. The study just actually halted for this analysis.

TARGETED ONCOLOGY: And then we also saw zanidatamab showing potential alone and in combination with chemotherapy as well.3 What are your thoughts on that agent and how it could can potentially impact the space?

GROTHEY: So zanidatamab, or ZW-25, is an interesting agent because it more or less combines trastuzumab and pertuzumab in one bi-specific molecule. So, targeting HER2 at 2 binding sites. Inhibiting ligand binding and more or less inhibiting dimerization. And so that is interesting, because we know from the My Pathway study, where we combined trastuzumab and pertuzumab, had significant activity in GI cancers. We know from breast cancer, that this combination is superior to trastuzumab. So, once we see more solid efficacy data, I think this is a very interesting agent, and it could mimic this approach we've seen in breast cancer. So, ZW-25 is very interesting.

There's another agent, which I think we need to talk about is margetuximab (Margenza), which is a HER2 antibody with an optimized Fc part. So, antibody and the immune system recruiting part, which already made inroads into breast cancer. And again, we were standing on the shoulders of giants in breast cancer when we talk about HER2 drug development in GI. And so, this also showed quite interesting data.4 And there's a larger study actually underway, the MAHOGANY study (NCT04082364) in gastric cancer, which also looks at the inclusion of a PD-1 inhibitor. So, the idea of double targeted agents, HER2 plus immunotherapy, I think it's quite interesting.

TARGETED ONCOLOGY: Are there other updates in either the GI cancer space or HER2-positive space that you'd like to mention that you think physicians should have their eye on for the future?

GROTHEY: ASCO GI showed a new potential targetable agent, which is FGFR2b overexpression in gastric cancer within an antibody called bemarituzumab.5 Bemarituzumab is an antibody against FGFR2b, which is overexpressed in about 30% of patients with gastric cancer, it was added to FOLFOX, a standard first-line treatment. A randomized trial compared FOLFOX, bemarituzumab to a placebo [with FOLFOX] (NCT03694522). And the initial data in this randomized phase 2 study with about 150 patients were quite interesting in terms of progression-free survival and overall survival. This is not phase 3 level of evidence, but it shows a potential new target, a new drug, and very intriguing outcomes in data so far, and it definitely justifies moving this into a phase 3, more definitive study.

TARGETED ONCOLOGY: In your own practice, how are you navigating the second- and third-line setting in colorectal cancer? What are some of the questions that we still have there?

GROTHEY: First of all, I strongly believe that patients benefit from access to all active agents. So, it's not should we use this one or the other, it's what's the best sequence that gives us the largest exposure to these agents. And on the other hand, the other important point is we're subdividing patients more and more into subgroups that have treatment relevance in colorectal cancer: microsatellite instability (MSI)–high tumors, BRAF- mutant tumors, POLE-mutant tumors, etc. So, these aside, the majority of patients with metastatic colorectal cancer is still being treated empirically. So, we're using FOLFOX, bevacizumab, or cetuximab (Erbitux) based on the RAS status, or panitumumab (Vectibix), and then moving them from line to line to line of therapy. And every line contributes to some degree. The outcomes benefit that patients have nowadays are really an accumulation of all these different steps that we add on top of each other.

Regorafenib (Stivarga) and TAS-102 (Lonsurf) are part of this treatment strategy, part of this treatment algorithm. So, they have different characteristics, regorafenib and TAS-102. Regorafenib, is not chemotherapy. It's an oral agent, like TAS-102 but it does not interfere with the bone marrow reserve, for instance. And when patients have, let's say, gone through 2 or 3 years of cytotoxic therapy, we see their blood counts go down, we need to use growth factors, whatever. So, wedging in a chemotherapy-free interval like regorafenib, in this whole treatment sequence might give patients a chance to have their bone marrow reserve recover, before they move on to TAS-102. It's posed as more traditional chemotherapy. The second point is that regorafenib is not an easy drug to use in terms of experienced toxicities. Patients notice this drug. I mean, fatigue, rash, blisters on their feet, especially if they don't take care of their feet. And if they're stuck with a higher dose of regorafenib, we shouldn't do any more.

So, dose-escalation strategies mitigate these side effects, but regorafenib is still subjectively more toxic than TAS-102 for most patients. That means you should not treat a patient with deteriorated performance status with regorafenib. I think the pool of patients that are candidates for treatment is larger with TAS-102 than with regorafenib. I will treat a patient with good [performance status score of 2] with TAS-102, but definitely not with regorafenib.

So how do I then optimize the treatment sequence realizing that patients can deteriorate their performance status from line to line of therapy just by tumor progression. So, I think there's a higher chance to really move exposed patients to regorafenib and TAS-102 is to use regorafenib first, followed by TAS-102. That's what I do most of my patients that are candidates for regorafenib.

Now, the other point is, I think the future of TAS-102 might actually be a little bit different. Yes, we have it as a third-line treatment option, a single agent. But we've seen data from 2 randomized studies where the combination with bevacizumab is quite intriguing. We've seen data from a Danish randomized study in the later-line setting that combination TAS-102 plus bevacizumab was better than TAS-102 alone with survival benefit actually, in an admittedly phase 2 study. But I think this is quite interesting because toxicities are not that much enhanced. We've seen ASCO GI data from the so-called TASCO1 study (NCT02743221) looking at TAS-102 plus bevacizumab, compared to capecitabine and bevacizumab in first-line treatment of patients who are not considered candidates for oxaliplatin and irinotecan.6 And again, TAS-102 plus bevacizumab performed very well. I mean, there is at least a numeric improvement in time-related outcomes. So that is a valid treatment option beyond using these drugs in a later-line setting. Perhaps we can use TAS-102 in an earlier line setting. And regorafenib, we're still struggling with the data of combination with nivolumab, which were really interesting at ASCO 2019. And It's not been validated since then. But I still believe there might be an opportunity to look at some select immune modulatory effects of regorafenib in combination with the right immune checkpoint inhibitors. So, the future might actually move these drugs out of the confined third-time setting into more interesting, earlier-line settings.

TARGETED ONCOLOGY: Are there any other important studies in the colorectal cancer field out of the ASCO GI meeting?

GROTHEY: One of the things that we have to highlight is KEYNOTE-177, the use of pembrolizumab in first-line MSI-high colon cancer in a randomized comparison.7 I mean, we all knew that this approach of a checkpoint inhibitor in highly mutated tumors actually would work. But we didn't have randomized data. And the trial definitely met its dual primary end point of progression-free survival and overall survival. So, we saw data of progression-free survival repeated at ASCO GI. The strong, long lasting effects, especially durability of responses is amazing. You know, when patients have response, they will continue to have response in 83% for 2 years. And I do believe that some patients actually might have a long term [no evidence of disease] situation. And eventually we might even be able to speak of cure in these patients. So, this is really a game changer for us. So, I'm very happy to see these randomized data. And the European Medical Agency also acknowledged that. So now pembrolizumab is available as first line treatment for these patients. So that's more or less worldwide. And that's a great achievement.

_References

1. _{FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA. January 15, 2021. Accessed April 2, 2021. https://bit.ly/39D40B0}

2. _{Raghav KPS, Yoshino T, Taniguchi H, et al. An open-label, phase II study of patritumab deruxtecan (HER3-DXd, U3-1402) in patients (pts) with previously treated advanced/metastatic colorectal cancer (CRC). J Clin Oncol. 2021;39(suppl 3):TPS157. doi:10.1200/JCO.2021.39.3_suppl.TPS157}

3. _{Meric-Bernstam F, Hamilton EP, Beeram M, et al. Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): Results from a phase I study. J Clin Oncol. 2021;39(suppl 3):164. doi:10.1200/JCO.2021.39.3_suppl.164}

4. _{Catenacci DVT, Rosales MK, Chung HC, et al. Margetuximab (M) combined with anti-PD-1 (retifanlimab) or anti-PD-1/LAG-3 (tebotelimab) +/- chemotherapy (CTX) in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction (GEJ) or gastric cancer (GC). J Clin Oncol. 2021;39(suppl 3):TPS264. doi:10.1200/JCO.2021.39.3_suppl.TPS264}

5. _{Wainberg ZA, Enzinger PC, Kang YK, et al. Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT). J Clin Oncol. 2021;39(suppl 3):160. doi:10.1200/JCO.2021.39.3_suppl.160}

6. _{Van Cutsem E, Danielewicz I, Saunders MP, et al. Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are noneligible for intensive therapy (TASCO1): Results of the final analysis on the overall survival. J Clin Oncol. 2021;39(suppl 3):14. doi:10.1200/JCO.2021.39.3_suppl.14}

7. _{Shiu KK, Andre T, Kim TW, et al. KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer. J Clin Oncol. 2021;39(suppl 3):6. doi:10.1200/JCO.2021.39.3_suppl.6}