The data that emerged from the phase 3 DESTINY-Breast03 trial (NCT03529110) represent a significant advancement in the field of metastatic HER2-positive breast cancer, said Adam M. Brufsky, MD, PhD, FACP, who added that the tripling of progression-free survival (PFS) seen with fam-trastuzumab deruxtecan-nxki (Enhertu) vs ado-trastuzumab emtansine (T-DM1; Kadcyla) will change the natural history of the disease.


“Clearly the DESTINY-Breast03 trial is the most practice-changing work that I’ve seen in HER2-positive disease,” said Brufsky, a professor of medicine at the University of Pittsburgh School of Medicine and associate division chief for the Division of Hematology/Oncology in the Department of Medicine.

Trastuzumab deruxtecan was initially granted accelerated approval from the FDA in December 2019 for patients with unresectable or metastatic HER2-positive breast cancer who received at least 2 prior anti­–HER2-based regimens in the metastatic setting.

 The regulatory decision was based on findings from the phase 2 DESTINY-Breast01 trial (NCT03248492), in which trastuzumab deruxtecan induced a median PFS of 19.4 months as a third-line treatment for patients with metastatic HER2-positive breast cancer who received prior T-DM1.

Findings from the DESTINY-Breast03 trial were presented during the 2021 ESMO Congress and subsequently published in the 

The study randomized patients 1:1 to 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks (n = 261) or 3.6 mg/kg of T-DM1 every 3 weeks (n = 263). Eligible patients had unresectable or metastatic HER2-positive breast cancer and were previously treated with trastuzumab (Herceptin) and a taxane in the metastatic setting. Notably, patients with clinically stable, treated brain metastases were eligible for enrollment.

At a median follow-up of 15.5 months, the median PFS by blinded independent central review was not reached with trastuzumab deruxtecan (95% CI, 18.5–not evaluable [NE]) vs 6.8 months with T-DM1 (95% CI, 5.6-8.2; HR, 0.28; 95% CI, 0.22-0.37; 

). The 12-month PFS rates were 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%), respectively.

Notably, median PFS was significantly improved across all subgroups evaluated, including for patients with brain metastases (n = 114; HR, 0.38; 95% CI, 0.23-0.64).

The median overall survival (OS) was NE in both arms; the 12-month OS rate was 94.1% with trastuzumab deruxtecan (95% CI, 90.3%-96.4%) vs 85.9% with T-DM1 (95% CI, 80.9%-89.7%; HR, 0.56; HR, 0.36-0.86; 

Regarding safety, the median treatment duration was 14.3 months with trastuzumab deruxtecan vs 6.9 months with T-DM1. The most common treatment-emergent adverse effect associated with treatment discontinuation with trastuzumab deruxtecan was interstitial lung disease (ILD)/pneumonitis, which occurred in 8.2% of patients treated. No grade 4 or 5 ILD/pneumonitis was observed.

Ultimately, the investigators concluded that the data from the DESTINY-Breast03 trial support trastuzumab deruxtecan as the standard second-line treatment for patients with HER2-positive metastatic breast cancer.

®, Brufsky, who is also the medical director of the Magee-Women’s Cancer Program of UPMC Hillman Cancer Center, associate director for clinical investigations at UPMC Hillman Cancer Center, and codirector of the Comprehensive Breast Cancer Center, discussed the significance of the data from DESTINY-Breast03 with trastuzumab deruxtecan vs T-DM1 for patients with metastatic HER2-positive breast cancer, as well as how the findings set the field up to improve outcomes for patients with brain metastases.

®: With all the data that emerged from 2021, what stands out to you as being the most practice changing?

: The biggest [development] that happened [in metastatic HER2-positive breast cancer] was the DESTINY-Breast03 trial. Clearly, it is a major advance. Those who are doing this work for, in my case, almost 25 years, we recall when the adjuvant trastuzumab [Herceptin] trials were presented in 2005. There was a separation of the curve of close to a 20% absolute difference in early-stage HER2-positive breast cancer from trastuzumab-based regimens and non–trastuzumab-based regimens.

What key findings were presented from the DESTINY-Breast03 trial?

The interesting thing here with DESTINY-Breast03 is that we now have with trastuzumab deruxtecan over a 25-month [median] PFS in the second-line setting vs 6.8 months with T-DM1. That truly is a tripling of PFS, which is clearly going to change the natural history of disease. That is the one thing that has changed practice for most of us in HER2-positive metastatic breast cancer.

Where do you anticipate research will be focused to further improve outcomes for patients with HER2-positive breast cancer?

We saw some very intriguing data from the 2021 San Antonio Breast Cancer Symposium that both trastuzumab deruxtecan and T-DM1 have some intracranial [efficacy]. In fact, brain metastases respond to these agents. [Brain metastases] are the other major [complication] that we worry about in patients with HER2-positive metastatic breast cancer; 50% or more patients will eventually develop brain metastases. If we have something that can treat [our patients with brain metastases], that will be another major advance that may be coming up.

FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. News release. FDA. December 20, 2019. Accessed January 13, 2021. 

Cortés J, Kim S, Chung W, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. 

. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741

Articles

Adam M. Brufsky, MD, PhD, FACP, discusses the significance of the data from DESTINY-Breast03 with trastuzumab deruxtecan vs T-DM1 for patients with metastatic HER2-positive breast cancer, as well as how the findings set the field up to improve outcomes for patients with brain metastases. 

Brufsky Underscores Practicing-Changing Data in HER2+ Metastatic Breast Cancer

Deborah L. Toppmeyer, MD, Chief Medical Officer and Director of the Stacy Goldstein Breast Cancer Center at Rutgers Cancer Institute of New Jersey, professor of medicine at Robert Wood Johnson Medical School, attending, Robert Wood Johnson University Hospital, discusses sequencing therapy in HER2-positive breast cancer.

Findings from the phase 3 CLEOPATRA trial (NCT00567190) established the combination of pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel as the preferred frontline standard of care for patients with metastatic HER2-positive disease. The regimen demonstrated an overall survival advantage compared with trastuzumab, docetaxel, and placebo.

In addition to evidence-based strategies, patient preference and their extent of disease should be considered when selecting treatment, Toppmeyer explains. Unlike the adjuvant and neoadjuvant settings where sequencing strategies are more established, several options may be considered for patients with metastatic HER2-positive disease, allowing treatment to be tailored to an individual’s needs, Toppmeyer says. 

Additionally, clinical trials should be considered as an option for eligible patients to further progress the field, Toppmeyer concludes.

Videos

Deborah L. Toppmeyer, MD, discusses sequencing therapy in HER2-positive breast cancer.



Dr. Toppmeyer on Sequencing Therapy in HER2+ Breast Cancer  

Ian E. Krop, MD, PhD, associate chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, clinical research director, Breast Oncology Center, senior physician, Dana-Farber Cancer Institute, associate professor of medicine, Harvard Medical School, discusses progress made in 2021 in the management of HER2-positive breast cancer.

The field of metastatic HER2-positive breast cancer is moving toward providing patients with long-term disease control and, theoretically, cure with the use of HER2-directed agents, antibody-drug conjugates (ADCs), and TKIs like tucatinib (Tukysa), Krop says. Optimizing treatment sequencing with these agents has the potential to eradicate all clones of metastatic disease. 

In the coming years, agents that proved highly efficacious in the metastatic setting may be found to have clinical utility in early-stage disease, Krop explains. For example, the ongoing phase 3 CompassHER2 RD Trial (NCT04457596) is evaluating tucatinib plus ado-trastuzumab emtansine (T-DM1; Kadcyla) vs T-DM1 alone to prevent relapses in patients with high-risk HER2-positive breast cancer. The ongoing phase 3 DESTINY-Breast05 trial (NCT04622319) is comparing fam-trastuzumab deruxtecan-nxki (Enhertu) with T-DM1 in high-risk patients with residual invasive disease following neoadjuvant therapy.

A goal of ongoing clinical trials is to find strategies to reduce the risk of patients with early-stage HER2-positive breast cancer developing metastatic disease, Krop concludes.

Ian E. Krop, MD, PhD, discusses progress made in 2021 in the management of HER2-positive breast cancer.  



Dr. Krop Discusses Progress Made in Metastatic HER2+ Breast Cancer 

The year 2020 saw a myriad of promising studies that resulted in several FDA-approved options for patients with metastatic HER2-positive breast cancer, said Sara A. Hurvitz, MD, who added that among the most exciting highlights were the data that read out from the phase 2 DESTINY-Breast01 trial (NCT03248492) with fam-trastuzumab deruxtecan-nxki (Enhertu).

FDA approval of the antibody-drug conjugate in December 2019

 in adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2–based regimens in the metastatic setting.

 presented during the 2020 San Antonio Breast Cancer Symposium indicated that trastuzumab deruxtecan elicited prolonged, durable responses and improved overall survival (OS) rates in this patient population.

With a median follow-up of 20.5 months, patients who received trastuzumab deruxtecan experienced a median duration of response of 20.8 months. Additionally, the estimated 12-month OS rate was 85% (95% CI, 79%-90%), whereas the 18-month estimated OS rate was 74% (95% CI, 67%-80%). Although the data are still immature, the preliminary median OS was 24.6 months (95% CI, 23.1 to not estimable [NE]). Patients experienced a median progression-free survival (PFS) of 19.4 months (95% CI, 14.1-NE).

“It's interesting to reflect on the fact that 20 years ago, Dennis J. Slamon, MD, PhD, of the UCLA Jonsson Comprehensive Cancer Center, and his colleagues, published the first-line data with trastuzumab in the metastatic setting; this was the first HER2-targeted agent,” Hurvitz explained. “In the trial, the median OS was about 2 years. It's interesting that we're seeing that in [DESTINY-Breast01] that patients had been treated with a median of 6 prior lines of therapy and achieved an OS of at least 2 years. These are very encouraging data.”

In an interview with OncLive®, Hurvitz reflected on key pivotal trials and recent regulatory decisions that have propelled progress in metastatic HER2-positive breast cancer. She is director of the Breast Cancer Clinical Research Program and codirector of the Santa Monica University of California Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, as well as an assistant professor of medicine in the Division of Hematology/Oncology of the David Geffen School of Medicine at UCLA.

What FDA approvals have we seen in HER2-positive, metastatic breast cancer over the past year?

Hurvitz: 2020 was an active year for [drug development in] HER2-positive, metastatic breast cancer. We had [4] FDA approvals, beginning in February 2020, when 

neratinib [Nerlynx] plus capecitabine was approved by the FDA

 for HER2-positive metastatic disease in the third-line setting and beyond. We had fam-trastuzumab deruxtecan-nxki approved as a single agent for patients who had been treated with 2 or more prior therapies in the metastatic setting based on the DESTINYBreast01 study. We also had 

the FDA approval of tucatinib [Tukysa] in combination with capecitabine and trastuzumab [Herceptin] in April 2020

 for use in the second-line setting and beyond, including patients with brain metastases. Most recently, in 

December 2020, we had the FDA approval of margetuximab-cmkb (Margenza)

It is an exciting time for patients who are diagnosed with metastatic HER2-positive breast cancer [with all these options].

With these new agents, how are you approaching sequencing decisions?

Sequencing is a trickier question because we don’t have a lot of data to inform that type of decision. Right now, we still use taxane trastuzumab/pertuzumab [Perjeta] in the first-line setting based on the CLEOPATRA study [NCT00567190]. Until a new agent goes head-to-head against this regimen, it will remain the frontline standard.

The second-line standard, based on level 1 evidence, is trastuzumab emtansine [T-DM1; Kadcyla] based on the EMILIA [NCT00829166] and TH3RESA studies [NCT01419197]. We do have the combination of tucatinib, capecitabine, and trastuzumab available for use in the second-line setting, but it wasn’t tested against T-DM1 in the HER2CLIMB trial [NCT02614794]. I would reserve the use of that regimen for patients who have central nervous system metastases.

tients who have central nervous system metastases. One of my colleagues, William J. Gradishar, MD, of the Northwestern University Feinberg School of Medicine, once called the third-line setting and beyond the Wild West. I love that analogy because it’s very true. We have so many regimens we can use, and sequencing [of these options] hasn’t been tested in a randomized clinical trial. [Right now], we sequence based on tolerability, the toxicity profile, and the data that we have relating to the agents. Many of us would use trastuzumab deruxtecan as our third-line agent of choice, but that may be moving up into earlier-line settings as new data accumulate from the phase 3 trials that are ongoing.

Would you like to spotlight any other pivotal data that read out last year?

Updated results from the DESTINY-Breast01 trial were presented at the 2020 San Antonio Breast Cancer Symposium; we now have around 20 months of follow-up. We do see an even better objective response rate of around 61% and a median PFS that is getting close to around 20 months. If anything, the results have gotten better with longer follow-up. A median OS of around 24 months was reached, but there weren’t a lot of events yet recorded. As such, I believe that the OS [data are] going to continue to evolve as more events accumulate.

FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. FDA. Published December 20, 2019. https://bit.ly/2tzcabv. Accessed January 7, 2021.

Modi S, Saura C, Yamashita T, et al. Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Poster PD3-06. 

Sara A. Hurvitz, MD, reflects on key pivotal trials and recent regulatory decisions that have propelled progress in metastatic HER2-positive breast cancer. 

Hurvitz Highlights Key Developments Made   in Metastatic HER2+ Breast Cancer Paradigm

Kristen K. Ciombor, MD, MSCI, assistant professor of medicine, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, discusses the FDA approval of fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-positive metastatic gastric cancer. 

 for the treatment of patients with locally advanced or metastatic HER2-positive gastric/gastroesophageal junction (GEJ) cancer who received a prior trastuzumab (Herceptin)-based regimen. The regulatory decision was based on findings from the phase 2 DESTINY-Gastric01 trial in which the antibody-drug conjugate improved overall survival and induced a higher objective response rate compared with chemotherapy in this patient population. 

Trastuzumab deruxtecan is a welcome addition to the gastric/GEJ cancer armamentarium, says Ciombor. However, as some patients will lose HER2 expression, routine biopsies are needed to determine whether the patient expresses the HER2 target and is still eligible to receive trastuzumab deruxtecan, Ciombor concludes. 

Kristen K. Ciombor, MD, MSCI, discusses the FDA approval of fam-trastuzumab deruxtecan-nxki in HER2-positive metastatic gastric cancer.  



Dr. Ciombor on the FDA Approval of Trastuzumab Deruxtecan in HER2+ Metastatic Gastric Cancer 

Suresh S. Ramalingam, MD, FASCO, deputy director, director, Lung Cancer Program, Winship Cancer Institute of Emory University, professor, assistant dean, Roberto C. Goizueta Distinguished Chair for Cancer Research, director, Division of Medical Oncology, Department of Hematology and Medical Oncology, Emory University School of Medicine, discusses the potential of HER2 as a driver mutation in non–small cell lung cancer (NSCLC). 

The positive effect of targeted therapies in lung cancer has become more evident with multiple FDA approvals, Ramalingam says. Moreover, 7 molecular targets in lung adenocarcinoma now have matched FDA-approved therapies that can be utilized to further personalize therapy to individual patients, explains Ramalingam. Taken collectively, data with these agents have shown response rates from 50% to 80% and median progression-free survivals ranging from 10 months to 25 months. Additionally, targeted therapies are mostly well tolerated among patients, Ramalingam says. 

As such, identifying novel targets for which no targeted therapies are currently available is a significant research effort in this space, Ramalingam explains. Around 1% to 2% of patients with lung adenocarcinoma harbor 

 mutations. However, as no targeted therapies are currently FDA approved for this subset, HER2 is a marker of clinical relevance and is being evaluated as a potential target in clinical trials, concludes Ramalingam. 

Suresh S. Ramalingam, MD, FASCO, discusses the potential of HER2 as a driver mutation in non–small cell lung cancer.  



Dr. Ramalingam on the Potential of HER2 as a Driver Mutation in NSCLC

Poziotinib, mobocertinib (TAK-788), and fam-trastuzumab deruxtecan-nxki (Enhertu) are among some of the agents that have positioned 

 as a must-test alteration in newly diagnosed advanced lung cancer, explained Lecia V. Sequist, MD, MPH, who added that the specificity of antibody-drug conjugates (ADCs) could challenge the broad activity of TKIs as a frontline standard in the near future.

“In the EGFR space where there are such established TKIs, ADCs are being thought of as salvage therapy, but if an ADC gets approved first for a certain indication, like 

 for example, then we’re really looking at a different paradigm where TKIs are then going up against ADCs. As a field, we could learn a lot by comparing and contrasting these different types of therapeutic approaches,” said Sequist.

, Sequist, the Landry Family Associate Professor of Medicine at Harvard Medical School, and director, Center for Innovation in Early Cancer Detection, Massachusetts General Hospital, discussed some of the advances that bore out in 2020 in 

-mutant lung cancer and previewed anticipated developments in 2021.

: Has HER2 joined the roster of genes to test for in advanced lung cancer? 

: HER2 has really become a much more widely recognized subset of lung cancer that we need to test for. One big lesson is that for patients with newly diagnosed advanced lung cancer, in particular advanced lung adenocarcinoma, we really need to do broad testing for a number of different mutations that have therapeutic implications, not just 

 mutations tend to [reside] in the exon 20 section of HER2, and HER2 is very analogous in its protein structure to EGFR. 

 mutations are therapeutically often treated with the same types of approaches as 

 exon 20 mutations, which is nice because a lot of the drugs do have activity in both genotypes. Some of the oral TKIs that work for 

 exon 20 insertions like poziotinib and TAK-788. 

The most exciting thing we saw in 2020 for [patients with] HER2 [mutations] was probably the results of the DESTINY-Lung01 study at the 2020 ASCO Virtual Scientific Program looking at an ADC. This [agent], trastuzumab deruxtecan, works just for [patients with a] HER2 [mutation]; it’s not appropriate for [an] 

 exon 20 [mutation]. The ADC has a very high response rate of about 60% in the frontline setting. For patients with this particular mutation, that’s a very exciting therapy, especially since it’s already FDA approved for patients with breast cancer.

What were your initial thoughts regarding the data with poziotinib and TAK-788? 

Poziotinib and TAK-788 are similar in that they have broad activity, not only over 

 too, and that leads to a lot of side effects like rash and diarrhea. The experience for patients with these drugs is similar to what we’ve seen in the past with the second-generation EGFR inhibitors, like afatinib [Gilotrif] and dacomitinib [Vizimpro], where you tend to get a good amount of rash and diarrhea and other skin and nail side effects, as well as oral side effects, that can be bothersome for patients. If that’s the only possible therapeutic approach, then there are ways to mitigate these side effects. However, if there are approaches that are more specific, more potent to just the mutant form of the proteins, and not the wild-type, or a totally different approach like an ADC that may have less toxicity, that’s really great for patients. 

The good thing about poziotinib and TAK-788 is they have really opened the door to treating new subsets of patients, which previously hadn’t been targeted specifically in clinical trials. I’m glad that there are now several companies and stakeholders going after this space, because there are a lot of patients with these mutations. If you test, you’ll find more and more [abnormalities], and having a personalized treatment option available is always a good thing.

How does trastuzumab deruxtecan stack up against these TKIs? 

For any genetically defined subgroup of lung cancer, if there is an approved therapy, that kind of catapults that to the head of the list. If [trastuzumab deruxtecan] does receive FDA approval, which I hope it does in the coming months, it’s certainly something that I would think about using in the frontline setting for patients with [a] 

 [mutation]. I have used the agent in some patients in the frontline setting as part of a clinical trial. It’s a great opportunity for these patients, and it really drives home the point that we need to test at the time of diagnosis, so that we are aware of which patients have this mutation.

What do you anticipate coming down the pipeline in 2021 in the HER2 space?

Novel TKIs are being developed that we haven’t seen results of. Some new TKIs, such as CLN-081, are being studied that we haven’t seen mature results on. For many of the genotypes, whether it’s EGFR or HER2, a space where there happens to be TKIs that can be effective and also ADCs that can be effective, we really aren’t sure how to sequence them. There have been few, if any, head-to-head studies of these two very different strategies.

Lecia V. Sequist, MD, MPH, discusses some of the advances that bore out in 2020 in HER2-mutant lung cancer and previewed anticipated developments in 2021.  

TKIs Set the Stage for Treatment in HER2-Mutant Lung Cancer, But May Be Eclipsed by ADCs  

INVESTIGATIONAL AGENTS FOR HER2-POSITIVE 

Investigational agents for HER2-positive gastrointestinal (GI) malignancies witnessed a surge of data in 2020 that could play a pivotal role in transforming treatment selection in the coming years, said Shubham Pant, MD. 

“In spite of COVID-19 [coronavirus disease 2019], many developments and discoveries were made in GI cancers in 2020,” said Pant. “We saw a lot of good early data in phase 1 and 2 trials in the HER2-positive setting. These newer agents, particularly the HER2-directed antibody-drug conjugates [ADCs] and bispecific antibodies, are really going to change the landscape of HER2-positive GI cancers, from gastric cancer to cholangiocarcinoma.” 

, Pant, an associate professor with a joint appointment in the departments of Investigational Cancer Therapeutics and Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed 2020’s most exciting updates in GI malignancies and spotlighted how 

 mutations are gaining traction as an actionable target in the space.

How will fam-trastuzumab deruxtecan-nxki (Enhertu) affect the treatment paradigm of gastric cancer, based on the data we’ve seen from the DESTINY-Gastric01 trial?

: Trastuzumab deruxtecan is an interesting therapy that showed good results in HER2-neu–positive patients who had previously been on trastuzumab [Herceptin]. [DESTINYGastric01 (NCT03329690)] was a randomized phase 2 trial comparing trastuzumab deruxtecan with chemotherapy in patients with HER2-positive gastric cancer. Interestingly, the median survival [with trastuzumab deruxtecan] was about 12.5 months versus 8.4 months with physician’s choice of chemotherapy. That translates to a hazard ratio of 0.59, which is statistically significant. That is what I found most compelling about the trial.

[Trastuzumab deruxtecan] is going to change the paradigm for these patients. [Moreover,] moving the ADC into the up-front setting is going to change the landscape.

Also, trials were reported in 2020 showing PD-1 inhibitors with chemotherapy and trastuzumab in HER2-neu–positive patients that showed very good response rates. We are looking at these frontline quadruplet combination regimens. Additionally, we are [awaiting] FDA approvals to use these compounds in the clinic in 2021. A number of other HER2-neu–targeted agents and small molecules that actually target the 

-neu mutation [are in the pipeline]. These have up-and-coming, early data.

Do you anticipate that HER2 will emerge as a relevant target in extrahepatic cholangiocarcinoma?

Gallbladder cancer and extrahepatic cholangiocarcinoma are more HER2-neu–positive compared with intrahepatic [cholangiocarcinoma]. We’ve launched the global trial targeting [HER2] with ZW25 [zanidatamab], which is a bispecific antibody. I’m really excited about the prospect of targeting HER2 in these rare malignancies. Just like 

 fusions came to the floor [in 2020], I am hoping 

-neu will be the story to be told in the next few years. 

We have other genomically targeted agents [under investigation], including [those directed toward] 

-neu. I am fairly excited about newer targeted agents coming into this field in 2021.

Zanidatamab received breakthrough therapy designation for patients with HER2-positive biliary tract cancer in November 2020. What is unique about that compound?

I’m one of the global leaders on this trial and have experience with [zanidatamab] in the phase 1 setting. Normally, secondline response rates in patients with cholangiocarcinoma are around 5%, as was reported with FOLFOX versus placebo. In our phase 1 expansion trial, although in a small number of patients, zanidatamab [induced] responses close to 50% in this population, which is very exciting.

What is your forecast for 2021 with regard to HER2-directed therapy in GI cancers?

Newer immunotherapies have the potential to change practice. Trastuzumab deruxtecan in patients with HER2-neu gastric cancer who were previously treated with trastuzumab will, hopefully, move forward in 2021. 

In HER2-neu–positive cholangiocarcinoma and gallbladder cancer, we recently launched a global clinical trial of [zanidatamab], trying to look for efficacy in the secondline setting.

: This interview took place prior to the January 15, 2021, FDA approval of trastuzumab deruxtecan for the treatment of patients with locally advanced or metastatic HER2positive gastric or GEJ adenocarcinoma who have received a previous trastuzumab-based regimen.

The field of HER2-positive gastrointestinal malignancies witnessed a surge of data in 2020 regarding investigational agents, such as the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki, that could play a pivotal role in transforming treatment selection in the coming years.

Fleshing Out HER2-Directed Therapies in GI Malignancies

Sara A. Hurvitz, MD, director of the Breast Cancer Clinical Research Program and co-director of the Santa Monica University of California Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, as well as an assistant professor of medicine in the Division of Hematology/Oncology of the David Geffen School of Medicine at UCLA, discusses the expanding HER2-positive metastatic breast cancer treatment arsenal.

Over the past year or so, several agents have emerged in the paradigm, according to Hurvitz. In December 2019, the FDA approved 

single-agent fam-trastuzumab deruxtecan-nxki

 (Enhertu) for use in patients who had received 2 or more prior HER2-based therapies in the metastatic setting. The regulatory decision was based on data from the phase 2 DESTINY-Breast01 trial. Then in February 2020, the FDA gave the green light to 

A couple of months later, in April 2020, the 

FDA approved tucatinib (Tukysa) plus capecitabine and trastuzumab (Herceptin)

 for use in the second-line setting and beyond, including patients with brain metastases. Most recently, in December 2020, 

margetuximab-cmkb (Margenza) plus chemotherapy

 received regulatory approval for those who had previously received 2 or more HER2-targeted regimens, at least 1 of which for metastatic disease, concludes Hurvitz.

Sara A. Hurvitz, MD, discusses the expanding HER2-positive metastatic breast cancer treatment arsenal.



Year in Review: HER2+ Updates in Oncology | Supplements and Featured Publications