Daniel Catenacci, MD

Evaluation of a Patient With Gastric Cancer

Considerations for Therapy in Gastric Cancer

Second-Line Treatment Options in Gastric Cancer

Beyond Second-Line Therapy in Gastric Cancer

HER2-Positive Gastric Cancer

Understanding the DESTINY-Gastric01 Trial

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

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



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

Stage IV gastric adenocarcinoma; ECOG 2



He was started on XELOX/CAPOX + trastuzumab

Dose reduced due to grade 2 diarrhea; unable to control after 4 cycles; discontinued treatment

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

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Daniel Catenacci, MD, reviews the case of a 71-year-old man with gastric cancer.

A 71-Year-Old Man with Gastric Cancer

 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 

 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 

 with amplification. That’s through a so-called bystander affect, where the drug is delivered to an area where there’s low-level 

 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 

 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.

Dr Catenacci discusses the DESTINY-Gastric01 study, including personal experience using trastuzumab deruxtecan.

 What is the utility of anti-HER2 therapy beyond progression in the first line? This comes on the back of anti-HER2 therapies being evaluated in breast cancer through later lines, which of course a number of studies have shown a benefit with even trastuzumab beyond first progression, lapatinib, T-DM1 [trastuzumab emtansine], etc. Even pertuzumab in the first-line setting, in addition to trastuzumab, and perioperative approaches. Breast cancer has had a lot of success with continued and altering of manners of inhibiting HER2.

On the other hand, unfortunately in gastroesophageal cancer, the first study, ToGA, did show a benefit, but a number of second-line studies and first-line studies have been negative. In the first-line setting, lapatinib plus chemotherapy was not shown to be better than chemotherapy alone for HER2-positive tumors in the LOGiC study.

Pertuzumab, added to chemotherapy plus trastuzumab, was not better than chemotherapy plus trastuzumab, although it trended, it was not statistically significant, and it’s not an improved indication for pertuzumab in the JACOB study. In the second-line setting we’ve had a number of studies beyond progression anti-HER2 therapy. The first was the TyTAN study, which was paclitaxel with or without lapatinib, which was a negative study, as well as the GATSBY study, which was T-DM1 versus taxane in the second-line setting, which was also negative.

We’ve also had a smaller phase 2 study that was randomizing to chemotherapy with or without trastuzumab beyond progression, and that study did not show benefit.

What we’ve learned though since those studies were done, and even during those studies, is that the mechanism of resistance to trastuzumab in the first-line setting for gastroesophageal cancer tends to be different than in breast cancer. In breast cancer, there are mechanisms that lead to resistance while the patient retains 

 amplification in their tumor cells, and signaling for HER2 is still dependent.

On the other hand, in gastroesophageal cancer, or at least a subgroup of them, there is evolution of the disease that is no longer HER2-dependent, it is no longer 

 amplified. If you rebiopsy the disease that’s progressing, it is HER2-negative if you do immunohistochemistry and FISH [fluorescence in situ hybridization] testing. The reason for that is because the biology of the cancer is different, and it’s heterogenous even within the patient. They have the same founder mutations and tumor suppressors, 

, etc, but then they have branched evolution, where only a subset of the disease is 

 amplified, while other components of the patient’s cancer are not.

When you treat with HER2 therapy in the first-line setting you can control those 

amplified clones, but the HER2-negative clones blossom and become the new burden of disease.

In all of the second-line studies that were done, it was assumed that a patient’s tumor was still 

 amplified because it was before first-line therapy, and that is at least partially responsible for why they have likely failed because up to half of the patients enrolled weren’t having HER2-positive disease.

The question of whether selecting patients for continued anti-HER2 therapy beyond first progression, if their cancer is still HER2 dependent, if is there a benefit from any of these anti-HER2 therapies, remains an open question.

Dr Catenacci highlights clinical trials in HER2-positive gastric cancer that may provide insight on differences in mechanism of resistance from one tumor type to another.

 After second-line therapy, we would follow similar principles in terms of when to switch from second to third line, even more so now there’s an even larger drop-off in clinical trials and databases in terms of what percentage of patients get to third-line therapy, where it’s less than 30% of patients. Going to fourth-line therapy, probably 10% or less will get to that point, and maybe 1% of our patients, those extreme outliers, will get to fifth line or higher.

What do we decide, and what are we doing at the time in third line after these patients that we’ve discussed, these 2 hypothetical patients who have received pembrolizumab, if they’re MSI [microsatellite instability]-high, and then started a general tract therapy of FOLFOX [folinic acid, fluorouracil and oxaliplatin] with paclitaxel, ramucirumab? Or in the HER2-positive setting of a patient who had FOLFOX [folinic acid, fluorouracil and oxaliplatin] with trastuzumab, then paclitaxel with ramucirumab. Now they’re progressing on their respective therapies, what would we do in the third line?

There are a number of standard approaches. The first and classic one would be to use whichever chemotherapy was remaining of the taxane or irinotecan, whichever one had not been used yet. Typically platinum in first line; 1 of the 2, irinotecan or taxane in the second line; and then the reverse in third line. That has always been a benchmark option there. The response rate there is not very good. It has a lot of room for improvement, but it’s a benchmark to compare to, and it’s about a response rate of 10%.

We also know that trifluridine, tipiracil, or Lonsurf, is an option based on the TAGS phase 3 study, which randomized patients in the third-line setting or higher, a global study, and showed a survival benefit with that agent. So that’s a known option as well in third line or fourth line if you were sequencing all of the regimens we just mentioned.

And then finally, based on the KEYNOTE-59 study, we know that pembrolizumab is an option for patients who have a combined positivity score [CPS] of PD-L1 of 1 or higher. That has been shown to be an incidence of around 60% of patients will have that score. And there’s certainly a known benefit to enriching with PD-L1–positive tumors. The response rates of PD-L1–positive tumors with that cutoff is around 13% for microsatellite stable tumors in the third-line setting or higher. It’s less than 5% for PD-L1–negative patients, and therefore it was not approved.

We also recognize that the higher the level of PD-L1, the better, and the more likely a patient will respond to immunotherapy checkpoint inhibitors that are monotherapy, especially. We have some choices in the third line that would be considered standard.

I would choose one of those chemotherapy versions for the most part, certainly for PD-L–negative tumors. But for PD-L1–positive tumors, we have the added option of pembrolizumab. And if they haven’t had immunotherapy earlier in their sequence course, then it could be considered here.

The reason why is because although the current standards are as I just mentioned, FOLFOX [folinic acid, fluorouracil and oxaliplatin] with trastuzumab for HER2-positive tumors in first line, or FOLFOX [folinic acid, fluorouracil and oxaliplatin] for HER2-negative tumors, there’s been a lot of activity in the first-line setting of this disease with a number of phase 3 studies evaluating FOLFOX [folinic acid, fluorouracil and oxaliplatin] chemotherapy plus a targeted agent. The CHECKMATE 649 study, which I had mentioned earlier, was FOLFOX [folinic acid, fluorouracil and oxaliplatin] plus nivolumab versus FOLFOX [folinic acid, fluorouracil and oxaliplatin] alone, an open-label study, a phase 3 study that the primary end point was for patients with a PD-L1 score of 5 or higher. That study showed a clear survival benefit and progression-free survival on response rate improvement, with toxicity. Grade 3/4 toxicity increased around 15%.

We expect this will become our new standard option in the first-line setting for a CPS of 5 or higher for all gastroesophageal adenocarcinomas. That’s a matter of time, and at the time of doing this presentation that has not occurred. But within the next several months, we do expect that to happen. Patients who have already received it in first line would not be indicated to continue it into later lines of therapy, say a third line where it had been previously been approved, except for those patients who have a PD-L1 score of 1 to 5, where typically they won’t be eligible in the first line, at least that’s anticipated. So in the third-line setting, after failing FOLFOX [folinic acid, fluorouracil and oxaliplatin] chemotherapy, then chemotherapy plus ramucirumab in the third-line or higher setting with a PD-L1 score of 1 to 5, one could consider doing that at that point, especially if the patient doesn’t have a heavy burden of disease, a maintained performance status, and not heavy symptoms because immunotherapy won’t work there no matter the PD-L1 score, especially if it’s really low level.

Daniel Catenacci, MD, discusses treatment options after second-line therapy, highlighting options for patients who are PD-L1 positive.

Daniel Catenacci, MD | Authors

Articles

A 71-Year-Old Man with Gastric Cancer

Understanding the DESTINY-Gastric01 Trial

HER2-Positive Gastric Cancer

Beyond Second-Line Therapy in Gastric Cancer