Antibody-drug conjugates ‘the next pillar of cancer therapeutics’
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After decades of developmental challenges, antibody-drug conjugates have emerged as potentially less toxic and more effective treatment options for a variety of malignancies.
Dozens of investigational antibody-drug conjugates (ADCs) are in the pipeline, and several approved ADCs are being evaluated as earlier lines of therapy and in head-to-head studies against current standard treatments.
Source: City of Hope Orange County
“This drug class has been around for quite some time — we just couldn’t make them safer and more effective,” Edward S. Kim, MD, MBA, FACP, FASCO, physician-in-chief for City of Hope Orange County and vice physician-in-chief for City of Hope National Medical Center, told Healio. “As the technology of biologics improved along with our understanding of how to target cell receptors, the approaches have become smarter and more savvy.”
Newer-generation ADCs are “game-changers for the treatment of certain solid tumors” because they allow for the delivery of more potent cytotoxic therapies directly to cancer cells without the need for strong expression of antigens by tumors, added Kim, a Healio | HemOnc Today Associate Medical Editor.
“People are looking at this as the next treatment platform,” he said. “ADCs with more potent payloads are an exciting breakthrough. It’s not the equivalent of humans traveling to Mars, but it is like the jump from an original Motorola flip phone to an iPhone.”
ADCs have piqued the interest of the oncology field due to their ability to provide substantial survival benefit for women with metastatic and otherwise difficult-to-treat breast cancer. This success spurred more development in hopes of further cracking the solid tumor treatment code — or at least making meaningful inroads where none previously existed.
Healio spoke with oncologists who have expertise in ADCs about the pronounced effect these agents are demonstrating in certain solid tumors, variations in toxicity profiles of these therapies, and the potential that use of this drug class for cancer treatment will expand.
A biological smart bomb
ADCs are targeted therapies comprising a monoclonal antibody that binds to cancer cells and is bound by a linker to a biologically active cytotoxic agent.
“It’s a hybrid of technologies put together in a way to maximize their effect while mitigating the toxicity,” Kim said.
Traditional cytotoxic chemotherapy damages all cells — cancerous and otherwise — whereas biologics are cell-signal directed and sometimes lack a strong killing effect depending on how important that signal is to the cell’s receptor, he said.
“On the other hand, ADCs don’t need much of a signal,” he added. “And with their attached payload, they can be directed like a guided missile to kill cancer cells.
“They are like a smart bomb in that they can direct their payload with precision and avoid excess damage,” he said. “We are using science to help deliver our more potent drugs while minimizing the side effects that can occur using traditional means.”
The ability to deliver a highly toxic agent directly into a cancer cell while potentially subjecting the body to less toxicity makes ADCs unique compared with other drug classes, according to Funda Meric-Bernstam, MD, chair of the department of investigational cancer therapeutics and medical director of the Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center.
“I’m excited about ADCs because I believe they are the next pillar of cancer therapeutics,” she told Healio. “They have shown remarkable activity across a variety of tumor types.”
She is particularly intrigued by the potential of ADCs for solid tumors.
“This is a very active area of drug development,” Meric-Bernstam said. “Enthusiasm about solid tumors started with successes in targeting HER2 in breast cancer, and rapidly we have seen remarkable efficacy from next-generation payloads — such as deruxtecan — thus enhancing antitumor activity and the ability to treat patients who have lower [target antigen] expression.”
Safety profiles vary
ADCs may act like biological smart bombs, but even the smartest bombs cause some collateral damage.
Treatment-related toxicities associated with ADCs mirror those seen with conventional chemotherapies but to a lesser degree.
A meta-analysis of 169 clinical trials involving ADCs showed a 91.2% (95% CI, 90.7-91.7) incidence rate for all-grade treatment-related adverse events, with 46.1% (95% CI, 45.2-47) of study participants experiencing grade 3 or higher adverse events.
The analysis identified lymphopenia (53%; 95% CI, 48.7-57.3), nausea (44.1%; 95% CI, 43.2-44.9) and neutropenia (43.7%; 95% CI, 42.6-44.9) as the most common all-grade treatment-related adverse events. Yet the authors cautioned about other related toxicities, including the potential for cardiopulmonary, ocular and skin-related issues.
“Different ADCs have different side-effect profiles,” Meric-Bernstam said. “Although ADCs are thought to be more targeted, there are still some side effects that differ based on the ADC.”
Toxicities are typically related to the payload or target, she said. She also urged clinicians to monitor for some of the more serious common toxicities certain ADCs present, such as ocular issues, neuropathy, cytopenias and interstitial lung disease (ILD).
“It’s important to have expertise when using these drugs and provide the appropriate monitoring and supportive care,” Meric-Bernstam said.
Gynecologic indications
Several ADCs have been approved for gynecologic indications.
These include tisotumab vedotin-tftv (Tivdak; Genmab, Seagen) — a tissue factor-directed ADC for women with recurrent or metastatic cervical cancer that progressed on or after chemotherapy — and mirvetuximab soravtansine-gynx (Elahere, ImmunoGen), indicated for women with folate receptor alpha-positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who received one to three prior lines of therapy.
Newly developed ADCs such as mirvetuximab soravtansine are a desperately needed treatment option, according to Jubilee Brown, MD, clinical professor at Wake Forest University and division director of gynecologic oncology at Levine Cancer Institute at Atrium Health.
“Unfortunately, most women with ovarian cancer experience disease recurrence and become platinum-resistant, so ADCs represent an opportunity for these women to use something potentially more effective during their cancer journey,” she told Healio.
Although more manageable than traditional chemotherapy, each ADC “has its own personality” and, therefore, a certain amount of toxicity, Brown said. Clinicians will need to educate both themselves and their patients about them before treatment begins, she added.
“ADCs can be administered at any infusion clinic with an adequate level of supportive care, provided the care team are educated on the toxicities that can develop and how to mitigate when necessary,” she said. "They do require a multidisciplinary team. For example, we have advanced practice providers, pharmacists and nurses who work closely together and with our patients to optimize our response to any toxicities."
Targeting HER2 for lung cancer
The evolving role of genomics and precision medicine in the treatment of lung cancer makes ADCs a natural fit for new drug development.
“The number of biomarkers that we standardly test for is more than any other field of oncology,” Kim said.
The current commercial use of ADCs in lung cancer is limited to a single accelerated approval indication for fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) — often referred to as T-DXd — for adults with HER2-mutant unresectable or metastatic
non-small cell lung cancer.
FDA based the approval on results of the multicenter, randomized phase 2 DESTINY-Lung02 trial. An interim analysis, presented at last year’s European Society for Medical Oncology Congress, showed T-DXd induced a confirmed objective response rate of 53.8% (95% CI, 39.5-67.8) among adults with previously treated HER2-positive metastatic NSCLC who received the highest dose evaluated during the study. Median duration of response had not been reached as of the data cutoff date.
Ongoing studies in lung cancer — including the confirmatory phase 3 DESTINY-Lung03 trial — are examining expanded use of T-DXd for patients with intermediate- or early-stage NSCLC, as well as for those with lower levels of HER2 expression.
“This is really exciting science,” Kim said. “We now can add HER2 mutations into our list of targetable biomarkers that we can test for among individuals with non-small cell lung cancer."
Toxicities related to treatment with T-DXd mirror those of typical chemotherapies, but to a lesser degree because of the way it is delivered, Kim said These include cytopenias, alopecia and nausea/vomiting.
T-DXd also has been associated with the development of pulmonary toxicity.
"Interstitial lung disease or pneumonitis is definitely something for clinicians to look out for,” Kim said, noting those who have used biologics before should be familiar with this type of treatment-related toxicity.
“Treating physicians should be cognizant that when patients appear to have trouble breathing, they should first stop giving the ADC and perform a thorough investigation," Kim said.
Other novel ADCs are in development for other targets, including HER3 and Trop2.
"Other than T-DXd, ADCs are only being given on clinical trials, but this is likely to change quickly given the number of agents in development plus the number of existing agents being evaluated for novel applications,” Kim said. “Right now, the focus is on trying to treat patients with incurable disease using either Enhertu alone or in combination with other approaches, but other indications will be forthcoming.”
‘The decade of the ADC’
Perhaps the most dramatic results observed thus far with ADCs in solid tumors have been in breast cancer.
ADCs are available for nearly all breast cancer types, according to Adam M. Brufsky, MD, PhD, FACP, professor of medicine at University of Pittsburgh School of Medicine, associate director for strategic initiatives at UPMC Hillman Cancer Center and a Healio | HemOnc Today Associate Medical Editor.
“Many of us have started calling the 2020s the decade of the ADC,” Brufsky told Healio. “Right now, we have two ADCs to treat triple-negative disease, but that is just the tip of the iceberg, with plenty more coming down the pike.”
The first indication for commercial use in breast cancer went to ado-trastuzumab emtansine (Kadcyla, Genentech) — also known as T-DM1 — in 2013 for adults with metastatic HER2-postitive disease.
Another ADC — sacituzumab govitecan-hziy (Trodelvy, Gilead Sciences) — is a Trop-2-directed agent approved for use in adults with advanced/metastatic triple-negative or hormone receptor-positive, HER2-negative breast cancer.
They are cornerstones in the development of ADCs for breast cancer, Brufsky said.
Meanwhile, the latest milestone in breast cancer therapy appears to be the deployment of next-generation payloads, such as that used in T-DXd, he added.
The heightened publicity of trials evaluating T-DXd in HER2-expressing solid tumors has been well deserved, Brufsky said.
“Seventy percent of all breast cancer can likely be treated with Enhertu,” he said.
Findings from the DESTINY-Breast02 trial presented at last year’s San Antonio Breast Cancer Symposium demonstrated the efficacy T-DXd compared with physicians’ choice of treatment for patients with treatment-resistant HER2-positive metastatic breast cancer.
Meanwhile, results of the DESTINY-Breast03 trial presented at the same meeting shifted the landscape in favor of T-DXd for HER2-positive breast cancer as the ADC of choice, more than doubling 12-month PFS compared with T-DM1, Brufsky said.
"More importantly, based on results from the phase 3 DESTINY-Breast04 study, Enhertu was approved for HER2-low disease,” he said. “It has a fairly high response rate in this setting, doubling the PFS as well as overall survival benefit."
Brufsky reiterated the importance of monitoring for ILD among those treated with T-DXd.
The decision whether to rechallenge those who have mild ILD symptoms is quickly becoming an important research question, Brufsky said.
Protocol calls for clinicians to stop ADCs when ILD symptoms arise. However, in cases when patients are stabilized and they show tremendous benefit from the drug, physicians and their patients now face a choice about whether to restart treatment, Brufsky said.
“If someone who develops interstitial lung disease is having a tremendous response to an ADC as fourth- or fifth-line therapy, then we need to weigh the risks and benefits of what we are doing against the potential toxicity,” he told Healio. "Right now, that’s the cutting edge of this business.”
Just the beginning?
If the 2020s are the decade of the ADC, how will their continued development impact cancer care moving forward?
Brown said she expects more of the same, with additional indications for gynecologic cancers as more targets are validated and newer, more powerful payloads are developed.
“ADCs have already had a huge impact on the treatment of ovarian cancer,” she told Healio. “They have opened up an entirely new segment of patients to the option for treatment.”
The convergence of ADCs and immunotherapies has led to “remarkable advances in the field of lung cancer treatment” over the past decade, Kim said.
The emergence of targeted ADCs has allowed lung cancer specialists to offer therapies as substitutions for traditional upfront cytotoxic chemotherapy.
“I would hope we continue to develop drugs to target specific markers and advance them into intermediate- and earlier-stage settings,” he told Healio.
There is similar enthusiasm in breast cancer.
“ADCs are already the standard of care for second- and third-line metastatic, HER2-low and triple-negative breast cancer,” Brufsky told Healio. “Everyone with metastatic disease in the United States will likely receive one of these drugs during their disease course.”
Brufsky also expects additional ADCs with novel antigen targets and payloads to be developed.
“The next 5 to 10 years will tell researchers a lot about resistance to ADCs and whether they can be given to patients one right after the other,” he said.
“I believe the future will see us move ADCs toward postoperative neoadjuvant use in place of traditional chemotherapy,” Brufsky added. “I think they will be expanded to the first line in metastatic [breast cancer], as well as into the post-neoadjuvant or adjuvant setting.”
Developing drugs that have a meaningful impact on patient outcomes is a difficult task, according to Meric-Bernstam.
“Regardless of the obstacles, many of the ADCs that have been approved over the last several years have had a profound effect on improving objective response rates and PFS, with some already showing benefits in OS,” she said.
If the advances seen in breast cancer are an indicator, Meric-Bernstam is eager to see what value ADCs can provide next for multiple solid tumor types.
“I believe that, over the next 5 years, we will see a significant change in our clinical practice and how we treat many of these diseases,” she told Healio. “This is likely just the beginning of what is possible in the ADC field.” – by Drew Amorosi
References:
- Goto K, et al. Abstract LBA55. Presented at: European Society for Medical Oncology Congress; Sept. 9-13, 2022; Paris.
- Hurvitz SA, et al. Abstract GS2-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2022; San Antonio.
- Krop I, et al. Abstract GS2-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2022; San Antonio.
- Zhu Y, et al. Cancer. 2023;doi:10.1002/cncr.34507.
For more information:
Jubilee Brown, MD, can be reached at jubilee.brown@atriumhealth.org.
Adam M. Brufsky, MD, PhD, FACP, can be reached at brufskyam@upmc.edu.
Funda Meric-Bernstam, MD, can be reached at fmeric@mdanderson.org.
Edward S. Kim, MD, MBA, FACP, FASCO, can be reached at edwkim@coh.org.
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