Manish A. Shah, MD, director of the Gastrointestinal Oncology Program within the Division of Hematology and Medical Oncology and the Center for Advanced Digestive Care at Weill Cornell Medical College/ NewYork-Presbyterian Hospital, discusses the updated results of the phase 2 DESTINY-Gastric01 study with fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-expressing advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The DESTINY-Gastric01 study was quite exciting, says Shah. This was a phase 2 study of the novel antibody-drug conjugate trastuzumab deruxtecan in HER2-positive gastric cancer. It was a 2:1 randomization where patients received either trastuzumab deruxtecan or physician’s choice of standard chemotherapy. 

The overall response rate was 51.3% in patients who received trastuzumab deruxtecan and a significant improvement in overall survival, with a 12-month OS rate of 52.1%. The median overall survival in the trastuzumab deruxtecan arm was 12.5 months versus 8.4 months in the chemotherapy arm (HR, 0.59; 95% CI, 0.39-0.88; 

Based on those findings, there is a lot of excitement about this drug and a global follow-up study is being conducted now, concludes Shah.

Videos

Manish A. Shah, MD, discusses the exciting updated results of the phase 2 DESTINY-Gastric01 study with fam-trastuzumab deruxtecan-nxki in HER2-expressing advanced gastric or gastroesophageal junction adenocarcinoma.

Dr. Shah on Updated Results With Trastuzumab Deruxtecan in DESTINY-Gastric01

Jaffer A. Ajani, MD, professor of medicine and an internist in the Department of Gastrointestinal Medical Oncology with the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the potential clinical implications of fam-trastuzumab deruxtecan-nxki (Enhertu) in gastric or gastroesophageal junction (GEJ) adenocarcinoma if approved by the FDA.

If trastuzumab deruxtecan is approved for HER2-positive gastric or GEJ adenocarcinoma, its clinical implications would be similar to other agents that have been approved in the later-line setting—all of which have been tried in earlier lines of therapy, says Ajani.

Based on the DESTINY-Gastric02 findings, a second-line indication could be in this agent's future, though it may also move to a first-line indication later on.

In the adjuvant breast cancer setting, ado-trastuzumab emtansine (T-DM1; Kadcyla), trastuzumab (Herceptin), and pertuzumab (Perjeta), have all made their way to the adjuvant setting. Trials start with heavily treated patients, then less heavily treated patients, before moving to the first-line, and then, eventually, the adjuvant setting. It's possible that the same could also happen in gastric cancer and lead to the approval of trastuzumab deruxtecan in the adjuvant setting, concludes Ajani.

Jaffer A. Ajani, MD, discusses the potential clinical implications of fam-trastuzumab deruxtecan-nxki in gastric or gastroesophageal junction adenocarcinoma if approved by the FDA.

Dr. Ajani on Clinical Implications of Trastuzumab Deruxtecan in Gastric and GEJ Adenocarcinoma

Fam-trastuzumab deruxtecan-nxki (Enhertu) has been shown to induce impressive response rates in the phase 2 DESTINY-Gastric01 study (NCT03329690), although questions remain regarding the agent’s safety in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma , according to Daniel Catenacci, MD.

FDA granted a breakthrough therapy designation

 to the antibody-drug conjugate (ADC) for the treatment of patients with HER2-positive unresectable or metastatic gastric or GEJ adenocarcinoma who have received 2 or more prior lines of therapy, including trastuzumab (Herceptin). The designation was supported by data from DESTINY-Gastric01.

 from the trial were presented during the 

. A total of 187 patients were included in the trial; 125 received trastuzumab deruxtecan and 62 received chemotherapy. Results showed that treatment with the ADC resulted in a higher objective response rate (ORR) of 51.3% compared with 14.3% in the chemotherapy arm. The median overall survival (OS) with the ADC versus chemotherapy was 12.5 months versus 8.4 months, respectively.

“[These were] remarkable outcomes that also translated to improved progression-free survival (PFS) and an improved OS [with trastuzumab deruxtecan] in this randomized study,” said Catenacci, an associate professor of medicine and director of the Gastrointestinal Oncology Program at the University of Chicago, as well as the assistant director of translational research in the Comprehensive Cancer Center. “I'm cautiously optimistic that this is a great option for patients.”

With regard to safety, the most common adverse effects of grade 3 or higher observed with the ADC included neutropenia, decreased appetite, anemia, thrombocytopenia, and decreased white blood cell count. Twelve patients experienced interstitial lung disease (ILD)/pneumonitis that was determined to be associated with the ADC per an independent adjudication committee; this event must be actively monitored and managed.

, additional experts provided their perspectives on the DESTINY-Gastric01 data, including:

Yelena Y. Janjigian, MD, a medical oncologist and chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center

Jaffer A. Ajani, MD, professor of medicine and an internist in the Department of Gastrointestinal Medical Oncology, of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center

These experts shared their insight on the efficacy and safety of trastuzumab deruxtecan in the gastric cancer space.

: Could you provide a brief overview of the phase 2 DESTINY-Gastric01 trial? What did it examine and what were the results of this research?

: We saw exciting results from the DESTINY-Gastric01 study at this year’s ASCO meeting that were simultaneously published in the 

. This was a randomized phase 2 study conducted in Asia and it [included] a heavily pretreated patient population in the third-line setting. [Patients] were randomized to receive chemotherapy or trastuzumab deruxtecan.

This was an important study because, [despite the fact that] heavily pretreated patients [often experience a] challenging disease course, the ORR was quite remarkable. The published literature shows a 51% ORR and a survival of 12.5 months, which is quite remarkable for this population and compares favorably with the standard of care. Based on these data, the FDA is now reviewing this drug for possible approval in the United States and [if approved, this agent] would really help our patients in the third-line setting.

The one concern with this drug is pulmonary toxicity; grade 5 events of toxicity-related deaths from ILD [were observed] in the breast cancer and colorectal cancer (CRC) data. In the gastric cancer arena, the literature suggests that although no grade 5 events were reported, the pulmonary toxicity is still an issue with this class of drug. We're eagerly awaiting the results of the United States data in this population, hoping to see that it's safe and confirmatory in the Western population, then we can use this drug in our patient population soon.

: The DESTINY-Gastric01 study is one of many within the DESTINY group of studies across various tumor types with the ADC trastuzumab deruxtecan. This was a study, specifically for gastric cancer, conducted solely in Asia in the third-line setting or higher. Fifty percent of patients with HER2-positive disease were [being treated in the] third line, and the rest were [receiving treatment in the] fourth and fifth line.

Notably, it was required that the [patients] were HER2 positive, but [samples] could be from an archived specimen, so it could have been from their pre–first-line therapy. Talking about molecular heterogeneity over time, we do understand that for many patients, one of their mechanisms of resistance to any therapy, including anti-HER2 therapy, is to select for HER2-negative subclones. The assumption that they were still positive from the first-line setting after 2 lines or more of therapy is not necessarily a true one. However, that being said, we don't know if the investigators of the studies still tried to select patients at the time of enrollment and check for HER2 positivity, either via circulating tumor DNA and/or a biopsy, which very well could have been done. We don't know that, especially at this time where we understand that this is a common problem. It'll be interesting to see and hear if that comes out later on, but it has not yet been reported.

: In my clinic, [when I am treating] a patient with HER2-positive disease in this setting, I don't target HER2 because [no agents have been] approved. I have to find a clinical trial [for that patient] or I need to treat them similarly to someone who may not have HER2 [expression]. In this trial, investigators obtained tissue and centrally confirmed that the tumor was still expressing HER2.

When you start looking at the end points [of the trial], the response rate was much higher [with trastuzumab deruxtecan]. You don't see a response rate [that high] in the third-line setting. We have nothing available in the clinic that produces such a high response rate, so that's very interesting. The duration of response [observed with the ADC] was also very long, which is another thing that doesn't happen. I can get a response in the third-line setting in my patient with chemotherapy, like [we saw in] the control arm, but it doesn't last very long. What’s unique about this molecule is that responses are high and they're durable, PFS is longer, and OS is also significantly longer. The hazard ratio was less 0.6 [with regard to OS], which is another thing you don't really see in the gastric space. For many years, every time we have succeeded with a new treatment, the advantage has been always minor. I am hoping that these data will be submitted to the FDA and that we will all be able to use this drug [in the near future].

What does the toxicity look like with the agent?

: The thing that we would have to look at and point out is that this is an Asian-only population, so is [these findings are] generalizable over to Western populations, which generally have worse prognoses. Many of these patients don't get to later lines of therapy. In addition to that, [we need to note the] toxicity rates; they have to be looked at. Although this is a targeted therapy; it comes with a cytotoxic agent conjugated to it. The toxicity rate of all-grade [events] was very high [with the agent]. Some pertinent grade 3 toxicities include neutropenia, but most importantly, pneumonitis or ILD, which is unique for the agent. [Approximately] 10% of patients experienced any grade of ILD, a quarter of whom had grade 3 or higher. In the colon studies and others, events of grade 5 pneumonitis were reported. We need to weigh these extremely good outcomes with the toxicity rates.

: Because there is so much chemotherapy attached to that antibody, it has unique toxicities. In breast cancer, lung cancer, and gastric cancer, ILD can occur in about 5% to 10% of cases; often it is lower grade, so patients will recover, but there have been some deaths reported. Of 125 patients on this trial, 3 were documented to have ILD and 1 patient died. When we use this drug, we will have to be very careful about selecting the right patient and then carefully monitor them.

What are the next steps for this research and does it leave any unanswered questions?

: The next step for the development of HER2-targeted agents is understanding how to best sequence them. Should we consider bringing some of these agents, such as the ADCs that are available on the market, into earlier lines of therapy? What's going to be the balance between the efficacy and toxicity? How do we best serve our patients and have them live a longer, symptom-free life and which patient population can we actually cure?

We've changed the biology of HER2-positive gastric/GEJ adenocarcinoma. We have had patients living with this disease for years. We're also seeing more and more unusual patterns of progression and escape patterns, particularly with a combination of anti–PD-1 and anti-HER2 therapy; this is because patients live for such a long time and do well. For the first time, we're seeing brain metastasis in the first-line setting, which is an unusual presentation for gastric cancer. TKIs such as tucatinib (Tukysa), which is a highly selected HER2 inhibitor, has been approved in breast cancer and is currently under development in gastric cancer. In CRC, it may be an interesting agent to study, as it does cross the blood–brain barrier. There has been excitement and resurgence in the HER2-positive field, so several agents will likely be approved and on the market within the year. As such, there is a lot of hope for our patients. It will be up to [us to determine] how to optimally sequence these [therapies] to improve outcomes.

: In the future, [toxicity] might make [the agent] more challenging to move it into earlier lines of therapy, where we already have good therapies available that induce similar response rates and survival rates, without this type of toxicity profile. Randomized data to appropriate controls in either earlier or later lines are going to be important in terms of understanding where to fit this drug in. However, in later lines for patients who are still HER2 positive who are in need of third-line treatment, our response rates for any therapy are quite low. If this agent [is further analyzed] in the Western population in large prospective studies, then this would serve as an excellent tool—even with that toxicity profile, when you weigh the pros and cons at that late stage.

If approved for this indication down the line, what would the clinical implications be?

: The orphan status is a great thing, but it doesn't necessarily mean it's going to get approved, per se. It may make some of the regulatory path a little bit easier, but in the end, the data we have are not enough to grant an accelerated approval, at least for the Western population. We need to see prospective data in [that] population, preferably randomized.

The ongoing DESTINY-Gastric02 trial, is a 72-patient, single-arm, phase 2 study that is being done in Western countries which is examining the agent in this patient population in the second-line setting. Patients are required to undergo a repeat biopsy to centrally confirm HER2-positive disease; that's the start. Whether or not a response rate of 50% compared with nothing is going to lead to an approval is another story; that would have to be weighed against the toxicity rate and the standard of care, which technically is paclitaxel and ramucirumab (Cyramza) and shows a response rate of 30%. Ultimately, the idea would be to have a randomized study before this is approved [for this indication].

: Based on the DESTINY-Gastric02 trial, the company will probably pursue a second-line indication. At a later date, [we] might [see it move to a] first-line indication. In the adjuvant setting in breast cancer, ado-trastuzumab emtansine (T-DM1; Kadcyla), trastuzumab, and pertuzumab (Perjeta), have all [made their] way to the adjuvant setting. You start with heavily treated patients, then less heavily treated patients, then the first line, and then the adjuvant setting, so that could also happen in gastric cancer.

What is your take-home message regarding this research?

: GEJ adenocarcinoma/gastric cancer is a very interesting heterogeneous disease and it's a challenge for both clinical trial development and for the patients and caregivers. The take-home message is to not give up. Participate in clinical trials, create exciting, novel trials asking important questions, and strive for a high bar of success. The days of incremental benefit and 2-month OS benefit should be behind us. These new targeted agents in selected patient populations demonstrate to us that some of our patients, even those with metastatic disease, can live a long life and potentially be cured; that’s what we should be striving for.

: The highest impact is going to be trastuzumab deruxtecan targeting HER2. This gives us some understanding of how we can use this target. If you can achieve such an advantage at a later line, there's a possibility you can add another drug like immunotherapy or another targeted agent that will not collide with this drug in terms of safety. There are many of possibilities.

Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: A randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). 

. 2020;38(suppl 15; abstr 4513). doi:10.1200/JCO.2020.38.15_suppl.4513

Articles

Experts share their insight on the efficacy and safety of trastuzumab deruxtecan in the gastric cancer space.

Experts Highlight Promise of Trastuzumab Deruxtecan in Gastric/GEJ Cancers

Salvatore Siena, MD, professor of medical oncology at Universita degli Studi di Milano and director of Niguarda Cancer Center at Grande Ospedale Metropolitano Niguarda in Italy, provides an overview of the DESTINY-CRC01 trial ​in HER2-positive metastatic colorectal cancer (CRC).

The phase 2 trial evaluated fam-trastuzumab deruxtecan​-nxki (Enhertu), says Siena. Trastuzumab deruxtecan isa​n antibody-drug conjugate with a cleavable tetrapeptide-based linker and a topoisomerase 1 inhibitor that has demonstrated activity in HER2-expressing cancers, Siena adds.

DESTINY-CRC01 enrolled patients into 3 cohorts, explains Siena. Cohort A enrolled 53 patients with either primary tumors or metastasized tumors expressing HER2 to a level of immunohistochemistry (IHC) 3+ or 2+ and in-situ hybridization (ISH)–positive, Siena explains. ​Cohort B evaluated 7 patients with IHC 2+ but in-situ hybridization–negative tumors. Finally, cohort C, made up of 18 patients, included those with IHC 1+ disease, Siena concludes.

Salvatore Siena, MD, provides an overview of the DESTINY-CRC01 trial ​in DESTINY-CRC01 trial in HER2-positive metastatic colorectal cancer.

Dr. Siena on the Design of the DESTINY-CRC01 Trial in HER2+ Metastatic CRC

Yelena Y. Janjigian, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses updated results from the ​phase 2 DESTINY-Gastric01 trial​ in previously treated patients with HER2-positive gastric cancer.

The multicenter study was conducted in Asia where heavily pretreated patients ​with HER2-positive disease were randomized to receive either chemotherapy or fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu). Despite the challenges, the overall response rate was remarkable, says Janjigian. Notably, the overall response rate was 51% ​with T-DXd versus 14% with chemotherapy. The median overall survival was at 12.5 months ​and 8.4 months, respectively.

These data compare favorably to several other standards of care, Janjigian explains. Moreover, due to the exciting data, a breakthrough therapy designation was granted to T-DXd by the FDA for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.

This would be extremely beneficial to our patients in the 3rd line setting, Janjigian exclaims. The risk of pulmonary toxicity is an area of concern with T-DXd as grade 5 treatment-related adverse events (TRAEs), including interstitial lung disease, have been observed in patients with HER2-positive breast cancer and colorectal cancer.

Yelena Y. Janjigian, MD, discusses updated results from the ​phase 2 DESTINY-Gastric01 trial​ in previously treated patients with HER2-positive gastric cancer.

2020 World GI: Updates in HER2+ GI Cancers | Supplements and Featured Publications

Dr. Shah on Updated Results With Trastuzumab Deruxtecan in DESTINY-Gastric01

Dr. Ajani on Clinical Implications of Trastuzumab Deruxtecan in Gastric and GEJ Adenocarcinoma

Experts Highlight Promise of Trastuzumab Deruxtecan in Gastric/GEJ Cancers

Dr. Siena on the Design of the DESTINY-CRC01 Trial in HER2+ Metastatic CRC

Dr. Janjigian on Updated Results from the DESTINY-Gastric01 Trial in HER2+ Gastric Cancer