ADC Toxicities: The Price You Pay for Efficacy

Neil Osterweil

September 29, 2023

Antibody-drug conjugates (ADCs) are revolutionizing care for patients with certain advanced solid tumors.

Currently, the FDA has approved six ADCs to treat various solid cancers, including breast, gastric, cervical, and platinum-resistant ovarian cancer, as well as another handful to treat a range of hematologic malignancies, including lymphoma. The indications for these drugs continue to expand to earlier stage disease and from mono to combination therapies.

The rationale for using ADCs in oncology is sound: design an antibody that targets an antigen found primarily in tumors but not normal tissues, link that antibody to a cytotoxic payload and, essentially, create a smart bomb that can unleash its cytotoxic fury onto a specific target.

But, even with this targeted design, ADCs often come with powerful side effects. Serious complications include myelosuppression, peripheral neuropathy, infections, neutropenia, thrombocytopenia, anemia, fatigue, diarrhea, nausea, vomiting, and liver enzyme abnormalities.

Given the growing number of patients receiving ADCs and the expanding indications for their use, understanding the toxicity profiles of these drugs, and developing strategies to mitigate and manage these side effects have become paramount, Paolo Tarantino, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues explained in a recent review exploring ADC toxicities and efforts to improve patient safety.

Inside the Toxicity Landscape

A range of factors can inform the type and severity of ADC toxicities a patient may experience.

In general, the toxicities associated with ADCs are related to their chemotherapy payloads, Tarantino explained.

The ADCs sacituzumab govitecan (Trodelvy) and trastuzumab deruxtecan (Enhertu), for instance, both incorporate a topoisomerase inhibitor as their toxic payload. The primary toxicities associated with these agents — alopecia, neutropenia, and diarrhea — align with the toxicities seen with unconjugated topoisomerase inhibitors.

Similarly, trastuzumab emtansine (Kadcyla), enfortumab vedotin (Padcev), mirvetuximab soravtansine (Elahere), and tisotumab vedotin (Tivdak), which have a microtubule inhibitor as the payload, come with similar toxicities to the microtubule-inhibiting drugs. These toxicities include alopecia, myelosuppression, diarrhea, and peripheral neuropathy.

"Therefore, payload selection can have major implications for the expected toxicity profile of ADCs," Tarantino and colleagues write in their review.

However, the linker and the antibody can also play into the type, incidence, and severity of ADC toxicities.

The antibody, for instance, may lead to adverse events from what's called on-target, off-tumor toxicities. These toxicities occur when the antibody engages nonmalignant cells that express the specific ADC target and cause the payload to accumulate at these sites.

One well-known example of on-target, off-tumor toxicity is ADC-related cardiotoxicity, which can occur with HER2-targeted drugs that use trastuzumab.

Serious, potentially fatal, side effects of ADCs can also occur when the manufactured molecules release their toxic payload too soon, or when the toxin diffuses not only in the tumor microenvironment but also in tissues outside the targeted region, causing what's called a bystander effect.

"The bystander effect is a double-edged sword," Aditya Bardia, MD, MPH, of Massachusetts General Hospital in Boston, told Medscape. "Newer ADCs have a bystander effect, which I think has contributed a lot to their efficacy." However, Bardia added, "it can also cause toxicity."

ADCs can come with some peculiar, less predictable toxicities as well, Tarantino added.

Patients who receive trastuzumab deruxtecan, for instance, may develop interstitial lung disease, which can be fatal. This "is probably the most important to remember because it means that the patient has to be monitored very carefully with CT scans of the chest more often than we would do with other treatments," he said. However, the mechanism to explain why some patients develop this adverse event remains unclear.

Another wrinkle, which makes adverse events harder to predict, is "drugs with similar targets or similar payloads don't always have identical toxicity," Bardia said.

One example of this is the investigational ADC datopotamab deruxtecan (Dato-DXd). Datopotamab deruxtecan targets Trop2, as does sacituzumab govitecan, and the payload is deruxtecan, like trastuzumab deruxtecan, but the most common side effect of datopotamab deruxtecan is mucositis, something generally "we don't see with either trastuzumab deruxtecan or sacituzumab govitecan," Bardia explained. In other words, "it's much more complex" than just the specific components of the ADC.

Approaches to Ease Toxicities

Given the broad range of ADC-related toxicities, experts have been exploring a host of strategies to improve the tolerability of these agents.

These include adjusting the chemistry of the ADC's antibody, linker, or cytotoxic payload, exploring optimized dosing strategies within clinical trials, and identifying biomarkers of toxicities in patients receiving ADCs to help predict and manage adverse events earlier.

Bardia explained that unexpected toxicities that crop up during early clinical trials have helped clinicians develop strategies to mitigate them. Such strategies include scanning frequently for pneumonitis in patients receiving trastuzumab deruxtecan, using prophylactic mouthwash to prevent mucositis associated with datopotamab deruxtecan and, for those receiving sacituzumab govitecan, providing granulocyte-colony stimulating factor to prevent neutropenia, as well as giving patients loperamide and antiemetics to treat diarrhea and nausea.

Finding an optimized dose for each ADC is also crucial for minimizing adverse events, Tarantino noted, citing early studies of trastuzumab deruxtecan in colorectal, lung, and other solid tumors in which the ADC, given at 6.4 mg/kg, was effective but also highly toxic.

"The FDA required a randomized study to compare the 6.4 mg/kg to the 5.4 mg/kg dose, and studies in both colorectal and lung cancer found that 5.4 was equally effective and less toxic," he said.

Tarantino and colleagues also suggest the use of wearable biosensors to identify and manage ADC-related toxicities sooner. Such devices could, for instance, provide real-time data on patients' heart rate, breathing, even oxygen saturation levels to identify early signs of interstitial lung disease.

Overall, "innovations in ADC design, pharmacogenomic testing and wearable biosensors as well as increased attention to the optimization of ADC dosing through dedicated prospective trials might help to leverage the potential of this highly promising class of anticancer drugs, which is still far from being fully explored," Tarantino and colleagues write.

The review by Tarantino and colleagues was unfunded. Tarantino has acted as an adviser and/or consultant for AstraZeneca, Daiichi Sankyo, Gilead, and Lilly. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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