Bassel El-Rayes, MD

Bassel El-Rayes, MD, director of the division of hematology and oncology, vice chair of clinical research, and professor of hematology and medical oncology at the University of Alabama at Birmingham, discusses how he approaches second-line therapy for patients with HER2-positive gastric cancer.

According to El-Rayes, the choice of second-line therapy for gastric cancer depends on the first-line therapy given, as well as whether the patient is HER2-positive. Other considerations include performance status, organ function, and other patient characteristics.

If a patient is HER2-positive, El-Rayes would use trastuzumab (Herceptin) plus a platinum-based agent such as cisplatin, 5FU [fluorouracil], or FOLFOX [leucovorin calcium, fluorouracil, and oxaliplatin] as frontline therapy. Following progression, the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) may be given in the second line for patients who have previously received trastuzumab.

El-Rayes says trastuzumab deruxtecan may offer advantages in disease control and survival over second-line chemotherapy options due to being an HER2-targeted agent. In the DESTINY-Gastric01 study (NCT03329690), it demonstrated improved efficacy and median overall survival benefit of 12.5 versus 8.4 months for physician’s choice of irinotecan or paclitaxel chemotherapy for patients with HER2-positive advanced gastric cancer.

 The things that affect the second-line therapy in patients with gastric cancer that are HER2-positive, as of course the choice of therapy in the front line, and the overall medical condition of the patient performance status, organ function, things of that nature.

 In my practice, when I approach patients with gastric cancer, one of the first things I look at is if they are HER2-positive. If they are HER2-positive, then [in the] frontline setting, I'm using trastuzumab plus a platinum-based tablet, like cisplatin, 5FU, or FOLFOX, or something of that nature. At the time of progression, I'm usually shifting over to trastuzumab deruxtecan, rather than going to another second-line chemotherapy like [paclitaxel] or ramicirumab. I feel like targeting the HER2 in the second-line setting provides advantage in terms of disease control and survivorship.

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Bassel El-Rayes, MD, discusses how he approaches second-line therapy for patients with HER2-positive gastric cancer. 

Choosing Second-Line Therapy for HER2+ Gastric Cancer

We are excited that the FDA recently approved trastuzumab deruxtecan for HER2+ [human epidermal growth factor receptor-2 positive] metastatic gastric and gastroesophageal cancer for patients who have progressed on a prior trastuzumab-based regimen. This was mainly based on the results of the DESTINY-Gastric01 trial, which compared trastuzumab deruxtecan to chemotherapy of choice by investigator. That trial showed significant improvement in terms of outcome in favor of trastuzumab deruxtecan in this population again. The trial included patients who had received 2 or more lines of therapy, but the approval from the FDA spans patients who have received prior trastuzumab without specification of the line of therapy, so it could be used in the second-line setting and beyond.

Our traditional approach for patients with HER2+ gastric or gastroesophageal junction tumors that are stage IV disease is to use trastuzumab plus a platinum-based therapy in the frontline setting. This is based on the ToGA trial. At the time of progression, we have traditionally treated patients similarly to the way we treat all other patients with gastric cancer using ramucirumab and paclitaxel. This approach in the second-line setting was heavily based on the fact that targeting the HER2 pathway in the second-line setting and beyond in gastric cancer had not been successful previously. Now with the results of the DESTINY-Gastric01 trial, we have an approach to target the HER2 pathway beyond the first-line setting. In my practice [at the Winship Cancer Institute of Emory University], I have tended to move trastuzumab deruxtecan to the second-line setting in patients who have failed frontline HER2-based therapy like trastuzumab plus a platinum regimen. This trial says that, in the second-line setting, you either continue to target the HER2/neu pathway, or you could use ramucirumab and Taxol [paclitaxel]. If you choose to use ramucirumab and Taxol [paclitaxel], then you should consider the trastuzumab deruxtecan in the third-line setting. As I said, in my practice, I feel like continuous targeting of the HER2 pathway in the second-line setting makes sense in this disease.

In my experience using this agent in the second- or third-line settings, it is an effective agent. It is relatively safe, and the adverse effects are relatively well controlled. The results of the DESTINY-Gastric01 trial, alongside my personal experience, indicate that this approach has a higher chance of disease control than using standard chemotherapy that is not directed against the HER2 pathway.

The main advice I would give regarding using trastuzumab deruxtecan in the second-line setting—this would apply also for using it beyond the second-line setting—is that one has to be careful about the adverse effect profile. Many of the adverse effects are adverse effects that we are used to managing such as problems with blood counts. Markers in cardiac function are also something we are used to doing with the trastuzumab use in breast cancer and gastric cancer. However, the adverse effect that is a bit unique for this drug is interstitial lung disease. We have to be aware of this potential adverse effect and be cognizant of it, and if patient presents with respiratory symptoms, we need to consider interstitial lung disease within the differential diagnosis because this is a known adverse effect of the drug. That adverse effect is not common, but we have to be aware and alert of it, and when patients present with symptoms, we need to consider it in our differential diagnosis and not directly assume that this is a viral or bacterial pneumonia but also consider interstitial lung disease from the therapy in the differential diagnosis. The last point I would say about the dose of the drug that is approved in gastric cancer is that it is different than the dose that is traditionally used in breast cancer. That is another thing that we have to keep in mind as we start using this drug more commonly in this clinical setting.

Case: A 66-Year Old Male With HER2+ Gastric Cancer

A 66-year-old man complains of a 4-month history of decreased appetite and diffuse abdominal pain

PMH: DM, medically controlled; colonoscopy at age 55 was unremarkable; no personal or family history of cancer

PE: bloating; abdominal pain on deep palpation; otherwise unremarkable


Labs: Hb 9.5 g/dL, plt 104 x 109/L; other lab values WNL

Endoscopy with biopsy: showed well differentiated papillary adenocarcinoma with invasion into the lamina propria

EUS: irregular borders on extraluminal surfaces with hyperechogenic spots

Abdominal/pelvic CT confirmed a 5.1 cm lesion with indistinct margins in the antrum of the stomach

Imaging showed 3 new small pulmonary lesions

Treatment changed to docetaxel + ramucirumab

Treatment was well tolerated for 4 cycles when he developed neutropenia

Patient was started on trastuzumab deruxtecan; repeat HER2 expression score was not indicated

Bassel El-Rayes, MD, an expert in oncology, discusses the DESTINY-Gastric01 trial of trastuzumab deruxtecan in HER2+ gastric cancer and comments on implications for second-line treatment and beyond.

Trastuzumab Deruxtecan for HER2+ Gastric Cancer

I would like to conclude by discussing the future directions and unmet needs in gastric cancer. Of course, there are a number of unmet needs in this disease. The therapy that we have has impacted survival of our patients, but unfortunately, the majority of patients with stage IV disease eventually progress and become refractory to all available therapies.

Therefore, we need more effective systemic therapies. One area of active research in the disease includes the role of immune therapy. Recently we’ve seen data suggesting immune therapy used with chemotherapy combinations may be beneficial in the frontline setting, specifically with nivolumab. Whether this approach will open the door for other immunomodulatory approaches in the frontline or second-line setting is still an area of active research.

In addition, it is important as we approach gastric cancer that we realize that it is not 1 disease but many diseases. Therefore, we must incorporate in our management plan a clear approach to select patients based on their molecular profile and recognize that we now have 3 biomarkers—MSI [microsatellite instability], HER2/neu, and the CPS [combined positive score], which is based on PD-L1expression. This biomarker profile keeps expanding and allows us to better select patients for therapies they would benefit from in the frontline, second-line, and third-line settings.

Future Directions and Unmet Needs for Gastric Carcinoma

: Now shifting gears to patients who are HER2/neu-positive in the third-line setting, we have recently seen data from the DESTINY-Gastric01 trial that have shown a benefit in attempting to retarget the HER2/neu pathway using a drug called trastuzumab deruxtecan, which is a trastuzumab molecule that is conjugated to a chemotherapy agent.

In the DESTINY-Gastric02 trial patients who were HER2/neu-positive at diagnosis were randomized on the third-line setting to either receive a chemotherapy of choice or this agent, and the trial showed an advantage of trastuzumab deruxtecan in terms of response rate, progression-free survival, and overall survival. Patients were not tested at progression for the HER2/neu overexpression, and data were used from the original tissue in the majority of patients.

The agent has a good safety profile, and the major toxicity observed in the trial was myelosuppression, in terms of neutrophils, red cells, or platelets.

In addition, a small subset, about 10%, of the patients developed interstitial lung disease and pneumonitis from this agent. While the pneumonitis was reversible in a majority of patients, it is an [adverse] effect that we have to monitor and watch for in patients receiving trastuzumab deruxtecan.

I have prescribed trastuzumab deruxtecan to a number of my patients. It is relatively easy to give, but you must monitor patients for toxicities, especially those reported in the study, including myelosuppression and interstitial lung disease. If you notice any evidence of interstitial lung disease, that would be an indication to interrupt therapy.

In the case that we presented today, this agent was used in the third-line setting in a patient who is HER2/neu-positive at the time of diagnosis.

We need additional research in order to move this drug earlier in the lines of therapy. In addition, one feature that was observed in the DESTINY trial is that patients who have higher expression of HER2/neu tend to respond better to this agent. So we need to look deeper into the role of the rebiopsies and potentially perform liquid biopsies in a better selection of patients.

These are questions that will be answered in future research. I use this drug in my practice along the lines that were described in the case: in the third-line setting in patients who are HER2/neu-positive at diagnosis.

Further, it is important as we approach patients with HER2/neu-positive gastric cancer to realize that the biology of HER2/neu-positive gastric cancer is not exactly the same as the biology of HER2/neu-positive breast cancer, where there is more experience in targeting that pathway. For example, we have learned that continuation of trastuzumab from frontline to second-line setting in gastric cancer was not beneficial. Similarly, other approaches of targeting this pathway, such as using pertuzumab and lapatinib, have not been effective in gastric cancer, but have shown effect in breast cancer.

The differences in the biology could explain the underpinning of this difference, including differences in the mechanisms of resistance to trastuzumab. These have been defined and worked out and include heterogeneity in the expression of the HER2/neu receptor in gastric cancer, and the heterogeneity in gastric cancer seems to be higher than in breast cancer. Therefore, there are differences between expression on the primary tumor and metastatic site.

Secondly, there is a subset of patients who may lose HER2/neu expression after treatment with trastuzumab, and that may present a challenge for targeting this pathway in the second- and third-line settings. The third mechanism of resistance that has been explored is the development of alternate signaling pathways. These would include MET or other signaling pathways that could result in redundant signaling, even if you block the HER2/neu pathway.

These 3 mechanisms of resistance may explain why many of these sequential strategies of targeting the HER2/neu pathway have not been as successful in gastric cancer in comparison to diseases like breast cancer.

The DESTINY-Gastric01 Trial and Mechanisms of Resistance in Gastric Carcinoma

What are the factors that impact my selection of frontline therapy? As we discussed earlier, the molecular profile impacts my selection. With patients who are HER2/neu-positive, I want to use trastuzumab plus chemotherapy in the upfront setting. Patients who are MSI [microsatellite instability]-high, I would consider an immune therapy approach. For patients who have a high CPS [combined positive score] I would consider a combination of immune therapy plus chemotherapy. Therefore, these molecular markers are key in selecting the path of therapy in the upfront setting.

Now the challenge is, unfortunately, that most patients progress, and when that happens we must look at the options available in the second-line setting. We have a number of chemotherapy regimens that have a proven track record in second-line settings. The most commonly used is a combination of a targeted drug called ramucirumab, plus a taxane, usually paclitaxel, or as was done in our case, docetaxel. In randomized trials this combination has shown to be beneficial in the second-line setting.

Other options in the second-line setting could include chemotherapy alone, such as a taxane or irinotecan. You could potentially use ramucirumab alone, which has shown to be beneficial in a randomized phase 3 trial as a single agent in the second-line setting.

So there are many treatment options for the second-line setting, and the choice in the front-line setting impacts the choice in the second-line setting. Of course, if you’re using FOLFOX [folinic acid, fluorouracil, oxaliplatin], you want to move over to a different regimen in the second-line setting.

The other things that can impact your choice in the second-line setting include patients’ performance status, organ function, as well as toxicities from the frontline setting that linger into the second-line setting, specifically neuropathy.

However, when patients progress in the second-line setting, what are the options in the third-line setting? In the third-line setting there are a number of options, and those are driven by the choice of agents used in the first-line and second-line settings, as well as the molecular profile of the patient.

Let’s start with the patients who are HER2/neu-negative. In the third-line setting, you are usually using another chemotherapy approach. Some of the agents that have shown activity in the third-line setting include a drug called TAS-102 [trifluridine, tipiracil], which is an oral agent that has shown benefit in a randomized trial.

Additional chemotherapy agents used in the third-line setting are agents like irinotecan, which have been used in smaller trials. If you haven’t used any of those agents in the frontline or second-line setting, you could potentially use them in the third-line setting.

Patients who have not been exposed to immune therapy in the frontline and second-line setting could potentially get immune therapy in the third-line setting, and we have data to show that approach has activity in that setting as well.

Treatment Options for Gastric Carcinoma

Molecular testing has become a key part of treating patients with gastric carcinoma, especially now that we understand not all gastric cancers are the same, and there are subgroups that require different treatment approaches. In my practice, I usually perform NGS [next-generation sequencing] on all patients with newly diagnosed stage IV gastric cancer.

In management, especially in the frontline setting, one of the biomarkers of importance is HER2/neu. Patients who have HER2/neu expression would benefit from chemotherapy plus trastuzumab, as is our case.

Another important marker is MSI [microsatellite instability]. Patients who have microsatellite instability would benefit from immune therapy in the upfront setting. Similarly, PD-L1 expression is measured by using the CPS [combined positive score], an important predictor for immune therapy response. This is especially important since immune therapy is becoming a more commonly used treatment in the upfront setting in stage IV gastric cancer.

Given the number of biomarkers that are key in making a clinical decision, I have found that NGS sequencing allows me to get the input on all these biomarkers plus additional biomarkers that may come into play in treatment selection.

Furthermore, liquid biopsies are available and have certain advantages over tumor biopsies. They are available when tissue is scanned or the biopsies are not of good quality for analysis, and they can be used serially to monitor changes in the molecular profile of patients as they progress from frontline, to second-line, to third-line therapy, making it more feasible than tumor biopsies. In my practice I tend to use both because I feel they complement each other.

In addition to the challenges of managing gastric cancer in 2020, we have to add the challenge of COVID-19 [coronavirus disease 2019]. In patients with gastric cancer, chemotherapy affects immunity, and that increases the risk of complications from infectious diseases, especially COVID-19. Therefore, as we plan the care of these patients it is key to make sure that we educate them about preventive measures for COVID-19, and encourage patients to receive vaccinations for the flu and other illnesses that can exacerbate COVID-19. Lastly, we want to ensure that our workplace is kept safe for patients who are accessing our work environment.

These are 3 steps that I have implemented to try to mitigate some of the risks of treating with chemotherapy and immune-suppressive agents during this pandemic.

Bassel El-Rayes, MD | Authors

Articles

Choosing Second-Line Therapy for HER2+ Gastric Cancer

Trastuzumab Deruxtecan for HER2+ Gastric Cancer

Future Directions and Unmet Needs for Gastric Carcinoma

The DESTINY-Gastric01 Trial and Mechanisms of Resistance in Gastric Carcinoma

Treatment Options for Gastric Carcinoma

Molecular Testing for Gastric Carcinoma