New Hope for Breast Cancer Warriors: ENHERTU Therapy Is A ‘Big Game Changer’ for HER2 Positive Metastatic Breast Cancer Patients

"I think that for a majority of patients and for physicians like myself who treat metastatic HER2 positive breast cancer, it’s going to lead to a paradigm shift in how we treat this patient population," Dr. Nancy Chan, a medical oncologist at NYU Langone’s Perlmutter Cancer Center, told SurvivorNet.

In the groundbreaking phase 3 trial, investigators compared ENHERTU (trastuzumab deruxtecan) with Kadcyla, also known as T-DM1, (trastuzumab emtansine). T-DM1 is the current standard of care drug for HER2 positive metastatic breast cancer patients that have already undergone first line treatment. The trial, which enrolled 524 patients in Asia, Europe, North America, Oceania and South America, is still ongoing, but early results have shown a very promising future for the drug.

The trial found that people treated with ENHERTU lived three times longer without their disease progressing than those treated with the standard of Kadcyla. Specifically, those treated with ENHERTU had a median PFS, or progression-free survival, of 25.1 months compared with 7.2 months for T-DM1. But the good news did not end there.

"If you look into the probabilities of response, which were also presented for both [drugs], it was 79 percent for ENHERTU compared to 34 percent," Dr. Ricardo Costa, a medical oncologist in the clinical investigator track at the department of breast oncology at Moffitt Cancer Center, told SurvivorNet. "And response to tumor shrinkage is really reduction in the centimeter size or the inch size of each lesion in the patient's body simple as that."

ENHERTU has also performed better as second-line treatment than when it has been administered as an already approved later-line treatment. When it comes to drug toxicity, for example, interstitial lung disease is a known potential side effect for ENHERTU. But this trial suggests that earlier use of the drug in patients who are less heavily pre-treated can affect the frequency and severity of this side effect.

"We saw here in the study that about 10.5 percent of the patients did get interstitial lung disease, but the majority were low grade so grade 1 or 2 which means that their underlying breathing was not so significantly affected that they cannot breathe or have to go on oxygen," Dr. Chan said. "This confirms that not only is this drug effective, it could be well tolerated especially when given in the earlier line setting."

Comparing the Two Drugs

T-DM1 and ENHERTU are both a type of drug called antibody conjugates, but the two are still very different.

"I would say that before ENHERTU came onto the scene, Kadcyla, or T-DM1, hit it out of the ball park," Dr. Chan explained.

Why, then, is ENHERTU performing better in this trial? The answer might lie in the differing construction of the drugs.

"You have more chemo attached per unit of trastuzumab," Dr. Costa said of ENHERTU while explaining that trastuzumab is the antibody for both drugs.

Dr. Ingrid Mayer, co-leader of Vanderbilt-Ingram Cancer Center’s breast cancer research program, thinks of it like a Christmas tree.

"If you have more ornaments, the tree looks prettier so [ENHERTU] ‘has more ornaments,’" she told SurvivorNet. "There's more drug-to-antibody ratio."

Emtansine is the payload, or chemo, for T-DM1, whereas durexecan is the payload for ENHERTU. Emtansine works by disrupting the ability that cells have to break apart from each other, whereas durexecan prevents the DNA from replicating to begin with which means that cumulative side effects are less of an issue. Neuropathy, or damage or dysfunction of one or more nerves that typically results in numbness, tingling, muscle weakness and pain, is an example of a cumulative side effect of T-DM1. This can lead to the need for patients to stop receiving the drug altogether or start requiring a lower dosage, but we don’t generally see that with ENHERTU.

"There's no real cumulative side effect," Dr. Mayer explained. "I mean the drug has side effects, all the drugs do, but there’s no cumulative side effect that typically requires a lot of dose reductions over time so potentially you're able to keep the drug going for a longer period of time."

ENHERTU is also designed to allow for easier access to the cell and more permeability. This leads to a “bystander effect” which allows the drug to seep through neighboring cells.

"It's a broader effect," Dr. Mayer explained. Think of like a bigger halo of effect of the drug that [ENHERTU] can have compared to T-DM1."

Because of this, cancers where the HER2 expression is not as strong have the potential for greater benefit from a drug like ENHERTU compared to T-DM1.

It is important to note, however, that there are certain risks for ENHERTU that don’t really exist for T-DM1, like interstitial lung disease.

"Only about two percent of patients had interstitial lung disease [for T-DM1]," Dr. Chan said. "This is in comparison to about 10 percent on this study. Now majority, again, were low grade, so manageable, but there is a significant difference. So, it’s important to remember that the standard of care drugs that we have they've been tried and true, they've been through these large randomized clinical trials previously."

Impacts of the Study

All three experts SurvivorNet consulted regarding this trial agree that these results are likely to change the standard of practice for HER2 positive metastatic breast cancer patients.

"This is what we all live for, right, to see studies like this which really are going to improve the lives of patients," Dr. Chan said. "We know that the standard of care drugs we use are effective, so don’t get me wrong, I’m not putting down the standard of care drugs especially one such as Kadcyla… but we don’t remain satisfied.”

Dr. Chan says that unless there’s a “highly compelling reason to avoid ENHERTU” like a patient who already had interstitial lung disease, for example, this drug is probably the “new go-to” in the second-line setting for HER2 positive metastatic breast cancer patients.

Dr. Mayer also emphasized that she had “no doubt” that this drug would translate into a “survival advantage” for these patients.

"As of now, the time that it takes for patients to progress on this drug when treated in second-line setting it’s unbelievably long, so much longer than it has been seen with T-DM1," Dr. Mayer said. "The trial has not formally reported the median amount of months that patients can stay on the drug, but it's a neighboring of possibly two-plus years whereas with T-DM1, it was only about seven months."

So, How Can Qualifying Patients Access this Drug?

Since ENHERTU is already FDA-approved, its new use should be implemented soon.

Dr. Chan said that buzz around a February release date is definitely possible given “how stunning these progression free survival curves” have been. Dr. Mayer thinks it could be even sooner.

"My guess it would be sooner than that because the drug's already available," Dr. Mayer said. "It really won't take long to just change the label."

But if you’re in the situation where this drug could potentially benefit you or a loved one right now or in the near future, it’s worth exploring your options and having conversations with doctors. Sometimes drug companies can even grant patients use of the drug even before its officially approved.

"There's data out there now presented at this meeting that people can use for peer-to-peer discussions with insurance payers that are not willing to let people use the drug a little earlier, but, as I said, because the drug is already available, this really could be something that can be deployed almost immediately," Dr. Mayer said.

Considering Clinical Trials

In the world of cancer, clinical trials make all the difference. And while it’s not every day that a clinical trial finds “practice changing results,” it is what they’re designed for.

"Clinical trials, in general, are the tool, the one tool, that we have to safely develop agents in terms of anti-tumor efficacy and clinical benefit and also to assess the safety profile of whatever agent in patients," Dr. Costa explained. "It allows for the patient to help advance science. That's the one true and tried benefit for society, right. So, it helps advance science and gives the patient the possibility of receiving treatments with greater clinical benefit."

Dr. Costa did warn, however, that going into a study does not necessarily mean better care.

"You may go into a study that may be worse than the standard of care," Dr. Costa said.

Clinical Trials for Breast Cancer

Dr. Chan echoed Dr. Costa’s thoughts, but says this trial serves as an example of why patients should consider all of their potential treatment options.

"For those patients who received or benefited from the ENHERTU arm of the study, they actually had early access to an effective drug," Dr. Chan said. "I think this is why we also talk to our patients about their treatment options that include standard of care and also to consider clinical trial as part of our treatment modality and to kind of dispel some of the stigma that surrounds clinical trials."

Understanding Different Types of Breast Cancer

Breast cancer has been the subject of much research, and treatment options vary greatly depending on a patient’s specific type of breast cancer. Nailing down the exact type of the disease requires looking into whether the cancerous cells have certain receptors. These receptors   the estrogen receptor, the progesterone receptor and the HER2 receptor can help identify the unique features of the breast cancer and help personalize treatment.

RELATED: Treatment for HER2-Positive Breast Cancer

"These receptors, I like to imagine them like little hands on the outside of the cell, they can grab hold of what we call ligands, and these ligands are essentially the hormones that may be circulating in the bloodstream that can then be pulled into this cancer cell and used as a fertilizer, as growth support for the cells," Dr. Elizabeth Comen, a medical oncologist at Memorial Sloan Kettering Cancer Center, tells SurvivorNet.

The Unique Features of Breast Cancer: Deciding the Right Course of Treatment

One example of a type of ligand that can stimulate a cancer cell is the hormone estrogen, hence why an estrogen receptor positive breast cancer will grow when stimulated by estrogen. For these cases, your doctor may offer treatment that specifically targets the estrogen receptor. But for HER2 positive breast cancers, therapies that uniquely target the HER2 receptor may be the most beneficial. Having metastatic HER2 positive breast cancer, like in the case of the study participants, means that not only is the HER2 receptor present on the outside of the cell, but that the cancer has spread beyond the breast.

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