Understanding the DESTINY-Gastric01 Trial

EP: 1.Evaluation of a Patient With Gastric Cancer

EP: 2.Considerations for Therapy in Gastric Cancer

EP: 3.Second-Line Treatment Options in Gastric Cancer

EP: 4.Beyond Second-Line Therapy in Gastric Cancer

EP: 5.HER2-Positive Gastric Cancer

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EP: 6.Understanding the DESTINY-Gastric01 Trial

Daniel Catenacci, MD: There is a novel agent called trastuzumab deruxtecan, which has been approved in breast cancer also in late-line [therapy]. This is an antibody-drug conjugate [ADC] that was studied there as trastuzumab backbone with irinotecan analogue conjugate, and it was also studiedin gastroesophageal cancer in the DESTINY-Gastric01 study.

This study was done solely in Asia, and it was a randomized phase 2 study. And the makeup of the patients were very late lines. About half of the patients were third line, and half were fourth line or higher.

To see third-line patients is only around 30% of our practice; fourth-line is about 10% of our practice, and so on. The question of whether these patients represent what we see more commonly is unknown. That said, this study, the primary end point was response rate, and secondary end points were survival and progression-free survival. This was a randomized study to physician’s choice of chemotherapy versus trastuzumab deruxtecan. And the response rate was clearly better in the trastuzumab deruxtecan arm after central review of responses. The final response rate was in the mid-40% range, which is good in the third-line or higher setting.

Progression-free survival and the overall survival were also clearly better compared to the control arm of chemotherapy alone. This study led to approval in Japan already, and is being done now in Western populations in separate studies. The DESTINY-Gastric02 trial, which has already completed accrual, is a single-arm phase 2 study in Western populations in the second-line setting. And importantly, that study required rebiopsy at the time of starting second-line therapy to confirm persistent HER2 amplification. That’s an important selection criteria. It’s going to help to enrich those who are most likely to benefit.

The mechanism of action of trastuzumab deruxtecan, as an antibody-drug conjugate, is to deliver this novel cytotoxic agent to cells harboring trastuzumab expression. Now there have been other ADCs around that we’re familiar with, like T-DM1 [trastuzumab emtansine], but this is a different linker that links the antibody to the drug, and it’s a different drug. Even though T-DM1 did not work well in this disease, that possibly at least contributed to the fact that we weren’t requiring a repeat biopsy to select for persistent HER2 positivity, but also because this is a different agent that’s conjugated to the trastuzumab.

In addition, there is some discussion, and some early data with small sample sets, that suggest that this trastuzumab deruxtecan molecule can even result in an effect in patients who have low levels of HER2 expression, not necessarily driven by HER2 with amplification. That’s through a so-called bystander affect, where the drug is delivered to an area where there’s low-level HER2 expression, and then it can diffuse to regional areas and have cell kill.

Whether that will bear fruit, we’ll need to see in larger sample sets. But clearly the drug is effective in HER2 highly amplified tumors in breast cancer, and there’s this phase 2 study in the randomized setting, in the third-line setting or higher in Japan, that has shown a signal there.

There’s also a DESTINY-Gastric04 study, which is a global randomized phase 2 study in the second-line setting with a control arm of paclitaxel and ramucirumab versus trastuzumab deruxtecan. That will be the pivotal study to confirm its role here in HER2-positive patients.

My personal experience with the drug, I did have the drug here as part of the DESTINY-Gastric02 study. We caught the tail end of that study, and we had a few screen failures of patients who were really sick and just couldn’t get on to the study before disease progression; and 1 patient did enroll.

That’s a good segue to the tolerability of the drug. It is a targeted therapy, so to speak, but it is also a chemotherapy that’s conjugated to it. If you look at the toxicity profile, it had a higher grade toxicity—grade 1, 2, and 3 or higher—than the control arm of chemotherapy alone.

There is a toxicity that is specific to this drug that is pneumonitis or interstitial lung disease [ILD], where about 10% of patients had any grade of ILD. And about a quarter of those were grade 3 or higher.

In the gastric studies, there have not been any grade 5 deaths from the drug, but in other studies in breast and in colon cancer there have been. This is a known, well recognized toxicity of the drug, and we have to pay attention to that.

In the third-line setting or higher, where classically response rates have been 10% or so, and as you get into later lines even lower, this agent would be a welcome addition to the arsenal we have, and counterbalance with the toxicity. But when you weigh the pros and cons in that setting, this drug will be welcome there.

On the other hand, moving it earlier into second-line and first-line therapy, where we have effective agents that don’t have these toxicity profiles, we need to see some head-to-head data to weigh the pros and cons and know what we’re getting into before moving forward with it.

In summary, we’ve talked about both the HER2-positive space and the HER2-negative space, which essentially, as a standard of care after first line, is similar, but we are now starting to see anti-HER2 therapies beyond progression, and assessment there. It’ll be interesting to see what these larger studies show and whether this becomes warranted.

The other thing to note is that immunotherapy is a common topic at this point in all cancers, including this one. What we’ve learned over the last several years with a number of studies, 10 or more phase 3 studies, is that immunotherapy can work very well in MSI [microsatellite instability]-high tumors, and that in patients who have PD-L1 scores that are 10 or higher at least, as monotherapy, it could be considered, especially if patients have low burden of disease, not very symptomatic, good performance status. That’s where you would want to do that.

But also we’ve now learned from ESMO [the European Society for Medical Oncology annual meeting], the first time we’ve seen chemotherapy plus immunotherapy, particularly in PD-L1–negative tumors, where what is being seen, even though the data have not fully been presented, are that patients that have higher PD-L1 scores are the ones who derive the most benefit. That’s where we expect the approval to be, in the CPS [combined positive score] of 5 or higher in the first-line setting.

Transcript edited for clarity.

Case: A 71-Year-Old Man With HER2+ Gastric Cancer

Initial Presentation

• A 71-year-old man complained of a 3-month history of abdominal pain and bloating, a sensation of fullness
• PMH: HTN, medically controlled; colonoscopy at age 53 was unremarkable; no family history of cancer
• PE: patient appeared tired, abdominal distention; otherwise unremarkable
  
  

Clinical Workup

• Labs: Hb 9.7 g/dL, plt 111 x 109/L; other lab values WNL
• Upper endoscopy with biopsy: showed an ulcerative lesion 5.8 cm mass in the cardia of the stomach; biopsy confirmed gastric adenocarcinoma
• CT of chest/abdomen/pelvis confirmed a 5.8 cm lesion with indistinct margins in the cardia of the stomach; 2 suspicious hepatic lesions
• EUS: gastric cancer lesion confirmed invasion of the muscularis propria
• Mutational testing: MSI high, PD-L1 0%, HER2 3+ by IHC
• Stage IV gastric adenocarcinoma; ECOG 2
  
  

Treatment

• He was started on XELOX/CAPOX + trastuzumab
  • Dose reduced due to grade 2 diarrhea; unable to control after 4 cycles; discontinued treatment
• Treatment initiated with a pembrolizumab
  • After 24-months of treatment without progression of disease pembrolizumab was discontinued
• The patient was started on trastuzumab deruxtecan; repeat HER2 expression testing was not indicated