Ten years ago, a new kind of therapy emerged for patients with advanced breast cancer. Its design was unusual: Chemotherapy had been chemically hitched to an immune molecule (or "antibody") that recognized and bound to HER2, a well-known protein on breast cancer cells. This strategic pairing allowed the chemotherapy, which was too toxic for systemic use, to be delivered in a highly targeted way, directly to tumor cells adorned with HER2 on their surfaces — like a potent, molecularly honed smart bomb.
Fast forward a decade, and now that trailblazing therapy, called trastuzumab emtansine or T-DM1, is one of several so-called antibody-drug conjugates (ADCs) in clinical use across a variety of cancer types. Over the last several years, scientists have learned how to enhance the construction of ADCs along multiple dimensions — improving the molecular linkers that join the antibody to its destructive payload, incorporating different forms of chemotherapy, and harnessing antibodies against a range of tumor targets. Now, ADCs are revolutionizing the treatment of breast cancer as well as lung cancer, ovarian cancer, and several other cancer types.
Sara Tolaney, MD, MPH
"Instead of going from one chemotherapy to the next, we now have a diversity of options to offer breast cancer patients that include multiple different antibody drug conjugates," says Sara Tolaney, MD, MPH, chief of breast oncology at Dana-Farber. "This is really an exciting new era."
Paradigm Shift in Breast Cancer Treatment
Dana-Farber scientists were among the early pioneers who helped pave the way for the use of ADCs in breast cancer. For example, the first in-human studies of T-DM1 were conducted at the Institute in 2009. Now, there are three FDA-approved ADCs currently being used to treat breast cancer: two (T-DM1 and trastuzumab deruxtecan, or T-DXd) employ the HER2-targeted antibody and carry distinct chemotherapy payloads, and a third, known as sacituzumab govitecan, utilizes an antibody against a protein called TROP-2.
"These are very sophisticated feats of molecular engineering that essentially allow us to use a very low dose of a very potent chemotherapy and enable that chemotherapy to be concentrated in the tumor," says Harold Burstein, MD, PhD, a breast oncologist at Dana-Farber.
Harold Burstein, MD, PhD
Dana-Farber researchers are pursuing a variety of clinical studies that continue to evaluate the effectiveness of these ADCs in different forms of breast cancer. One line of investigation involves T-DXd. With its HER2-seeking antibody, it was initially approved for use in HER2-positive breast cancers. But recent evidence shows that the treatment is also effective in some tumors that possess very low levels of the HER2 protein. Now, clinical trials are underway to determine if T-DXd can even destroy tumors that have barely detectable HER2 levels — a subset dubbed "HER2 zero."
"This is really a paradigm shift in how we think about treating breast cancers," says Tolaney. "We used to be so focused on finding oncogenic drivers — the mutated genes that fuel cancer growth — and figuring out how to turn them off. But now, the data are telling us we just need to find a little bit of target that's hanging out on the cell. And because we can deliver so much chemo, it'll work much better than anything else. It's changing the way we develop drugs and the way we think about cancer."
ADCs are heralding a new era of treatment in breast cancer. While the therapies were initially developed for fairly narrow indications — for example, advanced or treatment-refractory forms, or a particular molecular subtype — they are now expanding into earlier lines of treatment and into much broader swaths of breast cancer patients.
"Although these new drugs are highly innovative and often effective, it's important to note that from a patient perspective they feel much like standard chemotherapy," says Burstein. ADCs are administered intravenously, just like traditional chemotherapy, and can cause side effects, including nausea, hair loss, and reduced blood cell counts.
And just like more traditional treatments, tumors can also evolve ways to outsmart ADCs. Scientists are just beginning to determine how ADC resistance develops, which likely involves two main mechanisms: avoiding the effects of the toxic payload, and modifying or reducing the levels of the protein target.
Now, Tolaney and her colleagues are launching a clinical trial that will examine the concept of resistance — and potential ways to overcome it — by using two different ADCs sequentially in breast cancer treatment. These ADCs include T-DXd and a new one under development called Dato-DXd (short for datapotomab deruxtecan). They carry the same chemotherapy payload but have distinct protein targets: T-DXd takes aim at HER2; Dato-DXd targets TROP2.
"This is one of the first trials to look at the question of ADC sequencing and resistance," says Tolaney. "Now that we have several ADCs in clinical use, we need to figure this out."
Exploring Other Therapy Options
Pasi Jänne, MD, PhD
Breast tumors are not the only examples of cancer cell growth driven by HER2. Some lung cancer cells are also fueled by mutant forms of the protein, suggesting that HER2-targeted ADCs could prove effective in patients harboring these tumors. Pasi Jänne, MD, PhD, who directs Dana-Farber's Lowe Center for Thoracic Oncology and the Chen-Huang Center for EGFR-Mutant Lung Cancers, has led clinical trials testing the effectiveness of T-DXd in patients with advanced forms of HER2-mutant, non-small cell lung cancer. The ADC proved effective and received regulatory approval in 2022.
"This is an important milestone, because it's the first targeted lung cancer therapy to be approved for patients with HER2-mutant lung cancer," says Jänne. These patients represent about 2 to 4% of lung cancer patients, and often do not respond to other forms of treatment, including immune therapies. Now, he and his colleagues are running a randomized trial that evaluates the use of T-DXd as a first-line treatment compared to standard chemotherapy.
Jänne's team is also investigating the use of another ADC, called patritumab deruxtecan (or HER3-DXd), which targets HER3, a relative of HER2. What makes this protein compelling from a treatment perspective is that it is expressed on the vast majority of lung tumors that carry mutations in the EGFR gene — an important therapeutic target whose activity is blocked by several drugs now in clinical use. However, HER3 does not participate in the same molecular pathway as EGFR, which means that interfering with HER3 function could offer a secondary path to kill lung tumors — and overcome resistance to EGFR-blocking therapies.
"Antibody drug conjugates are filling important niches where we need new therapies," says Jänne. "This is an exciting area of drug development and there is a wealth of molecular targets that could be amenable to the approach." In addition, Dato-DXd is being tested in lung cancers in various clinical trials at Dana-Farber. ADCs are also being studied in combination with standard lung cancer therapies, including the EGFR inhibitor osimertinib and immune checkpoint inhibitors.
Ursula Matulonis, MD
ADCs are also making inroads in other forms of cancer, including gynecological cancers. Dana-Farber's Ursula Matulonis, MD, chief of gynecologic oncology, and her colleagues have been investigating an ADC called mirvetuximab soravtansine that recognizes the folate receptor alpha (FRalpha) and is linked to a chemotherapy drug called DM4. In November 2022, based on the SORAYA study, this ADC was granted accelerated approval from the U.S. Food and Drug Administration for use in patients with advanced forms of platinum-resistant ovarian cancer which express FRalpha. Nearly 35% of patients with high-grade serous ovarian cancer express FRalpha at high levels and these levels remain fairly consistent throughout the course of the disease. Based on the results of the SORAYA study, FRalpha is a compelling therapeutic target for platinum resistant ovarian cancer. Additional trials testing mirvetuximab soravtansine in other clinical situations for patients with ovarian cancer are underway.
One such trial is investigating pairing mirvetuximab soravtansine with bevacizumab, a drug that blocks blood vessel growth. The combination yielded encouraging results in a phase 2 study in patients with platinum-resistant ovarian cancer whose tumors express lower levels of FRa, underscoring the concept that high levels of a protein target are not always a hard-and-fast requirement for ADCs to work. Another trial is underway that explores combining mirvetuximab soravtansine with an immune checkpoint inhibitor in patients with recurrent high-grade serous endometrial cancer.
"Antibody drug conjugates are opening up a whole new and very exciting avenue for therapy besides traditional chemotherapy, with the benefit of being able to predict which patients will have the highest likelihood of success based on their tumor's expression levels of certain targets," says Matulonis.
Investigating Options in Blood Cancers
Shayna Sarosiek, MD
Dana-Farber researchers are exploring how ADCs can improve outcomes in other forms of cancer, including rare blood cancers such as Waldenström's macroglobulinemia. Researchers led by oncologist Shayna Sarosiek, MD, have launched a clinical trial evaluating the use of an ADC called loncastuximab tesirine, which targets the CD19 protein.
In Waldenstrom's, white blood cells in the bone marrow grow uncontrollably. These cells share molecular features of multiple white blood cell lineages, including lymphocytes and plasma cells. Importantly, in this condition, both of these cell types express the target protein CD19.
"Luckily, patients with Waldenström's have a long life-expectancy, so we have the luxury of treating them over many years," says Sarosiek. "But that also means we need to have more treatments in our therapeutic arsenal that are effective over their lifetime."
Typically, Waldenström's patients are treated with one of two standard therapies — either a chemotherapy-drug combination given over the course of a few months or an oral, molecularly targeted drug that is administered until disease progression. When those treatments cease to work, clinicians and their patients are faced with few options. The loncastuximab tesirine trial signifies an important opportunity to expand those treatment options.
Paul Richardson, MD
ADCs have also become a promising treatment option in multiple myeloma, another type of blood cancer. Dana-Farber researchers led by Paul Richardson, MD, Kenneth Anderson, MD, and others, including Clifton Mo, MD, and Monique Hartley-Brown, MD, MMSc, have been studying the effects of belantamab mafodotin (or belamaf for short) for roughly a decade. The drug initially won accelerated approval in the U.S. in 2020 for patients with advanced forms of multiple myeloma, but was removed from the market some two years later after an unsuccessful phase 3 confirmatory trial — although the drug remains in use in Europe following full approval by the European Medicines Agency. Another phase 3 trial, called DREAMM8, has recently been completed and results are eagerly anticipated to support the commercial re-introduction of belamaf in the U.S.
Belamaf targets an important protein on multiple myeloma cells, called BCMA, which is present at high levels on multiple myeloma cells but largely absent from healthy cells. The drug is given to multiple myeloma patients as an infusion every six to 12 weeks. Its chemotherapy payload, mafodotin, causes some irritation in the eye, but this side effect can be managed with eye drops, modifying ADC dose, and extending schedule.
Richardson and his colleagues are currently leading an international platform trial called DREAMM5, which explores strategic pairings of belamaf with other novel drugs. That includes a drug called nirogacestat; it upregulates BCMA and allows belamaf to be used at lower doses, with fewer side effects.
"By combining belamaf with other drugs, particularly ones that augment the immune system such as pomalidomide, we can make belamaf work even better," says Richardson, who leads clinical research at Dana-Farber's Jerome Lipper Multiple Myeloma Center. "What this means is that in advanced multiple myeloma patients, we can achieve high response rates and an average of two years of disease-free survival based upon recent data."
The results are noteworthy because they are similar to what can be achieved with currently available highly active BCMA-targeting therapies — which include personalized immune cell therapies (such as CAR T cells) and bispecific antibodies. These usually require hospitalization and can cause significant side effects.
"Multiple myeloma remains an incurable hematologic malignancy," says Richardson. "There is also a significant fraction of patients who are not served by existing therapies or eligible for some of the more complex immunotherapies. In this context, belamaf offers a very promising therapeutic option which is readily applicable to real-world practice, and is effective in particular in combination with currently approved treatments."
As Dana-Farber researchers continue to pursue clinical studies of ADCs across a variety of cancer types and drug combinations, they are optimistic and enthusiastic about the future.
"ADCs are surprisingly versatile and robust," says Burstein. "There are scores of new ones now under development, so it will be very exciting to see where this new wave takes us."
