MD Anderson at ESMO

Antibody drug conjugates have existed for years, but several recent advances are helping to refine how these cancer drugs work, expanding our understanding to help overcome their challenges and, ultimately, extending their benefit to more patients.

“Antibody drug conjugates are an exciting field of drug development,” says Funda Meric-Bernstam, M.D., chair of Investigational Cancer Therapeutics.

Antibody drug conjugates target cancer cells with a powerful punch

Potent cancer drugs are typically unable to differentiate cancer cells from normal ones. Antibody drug conjugates overcome this challenge by linking the drug to a monoclonal antibody specifically chosen to target and deliver the drug to cancer cells.

“We conjugate a cancer drug, such as a chemotherapy that’s highly toxic, to an antibody that targets a protein on the surface of a cancer cell,” says Meric-Bernstam. “The thought is that by delivering much higher concentrations of chemotherapy to cancer cells, we have a greater therapeutic index.” Because the drug payload is directly carried to the cancer cell, it reduces the side effects a patient may experience.

Antibody drug conjugates are administered intravenously, and the frequency of treatment depends on the specific drug. Many antibody drug conjugates are being used or explored to treat metastatic disease, and patients continue to receive infusions as long as they’re benefitting from treatment.  However, antibody drug conjugates are also being explored to treat patients with earlier stage disease.

HER2 serves as a target for antibody drug conjugates across several cancer types

The first antibody drug conjugate used to treat solid tumors was T-DM1, a combination of the HER2 protein-targeting monoclonal antibody trastuzumab and a chemotherapy drug called DM1.

T-DM1 is approved to treat metastatic breast cancer with overexpression of HER2, meaning there are high levels of HER2 protein on the surface of the cancer cell. It’s also approved to treat breast cancer with HER2 amplification, which means there is a higher-than-normal number of copies of the HER2 gene.

The level of HER2 expression of a tumor cell is determined by an immunohistochemistry (IHC) test. HER2 positive cancers are defined as either IHC 2+ with amplification or IHC 3+, with the higher number of IHC denoting a higher level of HER2 protein.

In addition to breast cancer, HER2 can also be found in several other types of cancers including stomach, lung, gynecologic and bladder cancers, but the levels of HER2 expression vary across tumor types.

DESTINY-PanTumor02 and other clinical trials aim to expand antibody drug conjugate benefit

The next evolution of HER2-targeting antibody drug conjugates came quickly with the introduction of the trastuzumab deruxtecan. Like T-DM1, it shows strong efficacy in tumors with high levels of HER2. But unlike T-DM1, it has also been shown to be effective against breast cancers with lower HER2 levels.

“Trastuzumab deruxtecan represents a rapid evolution in antibody drug conjugate technology that may be more efficacious. It has opened the door for many more patients to potentially benefit from these treatments,” says Meric-Bernstam.

Trastuzumab deruxtecan is currently approved by the Food and Drug Administration (FDA) to treat patients with HER2 positive breast cancer, HER2 low breast cancer (HER2 2+ or 1+ tumors without amplification), HER2 positive gastric cancer and HER2 mutant lung cancer.

Yet patients with more difficult-to-treat HER2-expressing cancers are without a targeted treatment option.

Meric-Bernstam is leading several clinical trials investigating antibody drug conjugates. One study is the DESTINY-PanTumor02 clinical trial, a multicenter basket clinical trial investigating trastuzumab deruxtecan in patients with solid tumors with IHC 2+ or 3+ levels of HER2 expressions.

New targets may lead to new antibody drug conjugate options for patients

The burst of development in antibody drug conjugates can be credited to the progression of the technology used to link the drugs’ components as well as it can be attributed to improvements to the efficacy of the payload drugs.

As antibody drug conjugates have evolved, more targets have been identified. “We now see multiple targets moving forward as well as different strategies to treat the same patient population,” says Meric-Bernstam.

For example, the TROP2 protein is overexpressed in several epithelial tumor types, including triple-negative breast cancer, hormone receptor positive breast cancer and bladder cancer. Sacituzumab govitecan is approved to treat patients with these TROP2 positive cancers, and other drugs, such as datopotamab deruxtecan, are being investigated to treat the same TROP2 positive cancers.

In addition, enfortumab vedotin has been explored to target tumors overexpressing the nectin protein. Although nectin is overexpressed in other tumor types, thus far the drug has been approved to treat patients with nectin positive bladder cancer.

Improved understanding will lead to better patient selection
Over the next few years, Meric-Bernstam expects several more antibody drug conjugates to emerge. “I think we’ll see multiple antibody drug conjugate options for patients,” she says.

New questions will arise as more antibody drug conjugates that target the same proteins in the same patient population are developed. To improve patient selection, Meric-Bernstam says more research is needed to:

• understand the influence of a protein’s expression level on the efficacy of the drug
• evaluate if and how previous treatment with a different antibody drug conjugates and other chemotherapies will impact efficacy and sequencing
• better predict patient response to the various payload options
• anticipate the potential side effects

Although side effects vary between the antibody drug conjugates, Meric-Bernstam warns there is still the risk of side effects related to bone marrow, lung inflammation and neuropathy. Lastly, she predicts that there will be more research exploring rationale combinations, too.

With so many advances made in the field in such a short time, Meric-Bernstam sees antibody drug conjugates as shifting the options for patients with difficult-to-treat solid tumors.

“We’ve seen so many antibody drug conjugates demonstrate benefit to patients with difficult-to-treat tumors that, in my mind, they’re the next pillar of cancer therapeutics,” says Meric-Bernstam.

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Combination immunotherapy with the anti-PD-L1 monoclonal antibody durvalumab and other novel agents outperforms durvalumab alone in the neoadjuvant (pre-surgical) setting for early-stage non-small-cell lung cancer (NSCLC), according to researchers from The University of Texas MD Anderson Cancer Center. 

The findings, published today in Cancer Discovery, were first presented at the American Association for Cancer Research (AACR) Annual Meeting 2022.

The multicenter, randomized Phase II NeoCOAST clinical trial evaluated neoadjuvant durvalumab alone and in combination with each of the following novel immunotherapies: the anti-CD73 monoclonal antibody oleclumab, the anti-NKG2A monoclonal antibody monalizumab and the anti-STAT3 antisense oligonucleotide danvatirsen. While the study was not statistically powered to compare arms, all combinations resulted in numerically higher major pathological response (MPR) rates than with durvalumab monotherapy.

“This study builds on the growing evidence that combination immunotherapy has a role in the neoadjuvant setting for this patient population,” said Tina Cascone, M.D., Ph.D., assistant professor of Thoracic/Head and Neck Medical Oncology and lead author of the study. “Ultimately, we want to give patients a chance to live longer without their cancer returning.”

The NeoCOAST trial adds to recent progress in neoadjuvant treatment for NSCLC, including the Phase II NEOSTAR study results that Cascone reported last year showing nivolumab and ipilimumab together induced higher responses than nivolumab alone, and the March 2022 approval of nivolumab combined with platinum-based chemotherapy from the Checkmate-816 study. The durvalumab combinations tested previously in the Phase II COAST trial were shown to be effective in unresectable stage III NSCLC, providing rationale for testing in earlier stage disease.

The NeoCOAST study enrolled 84 patients with untreated, resectable (>2cm), stage I-IIIA NSCLC, between March 2019 and September 2020. Most patients were male (59.5%) and had a smoking history (89%). The median age was 67.5, and the racial breakdown was 89% white, 6% Black, 2% Asian and 2% other. Eighty-three patients received one 28-day cycle of neoadjuvant durvalumab alone or combined with another therapy.

The primary endpoint was investigator-assessed MPR, defined as ≤10% residual viable tumor cells in the resected tumor tissue and sampled nodes at surgery. The investigators assessed pathological complete response (pCR), or complete disappearance of viable tumor cells, as a secondary endpoint. Exploratory endpoints included tumor, fecal and blood biomarkers.

All combinations had numerically higher rates of MPR and pCR than monotherapy, and there were no statistically significant differences in responses between the combination arms:

• For the patients who received durvalumab monotherapy, MPR occurred in 11.1% and pCR in 3.7%, which is comparable to results from other monotherapy studies.
• MPR rates for combination therapy ranged from 19% (oleclumab) to 31.3% (danvatirsen), and pCR rates ranged from 9.5% (with oleclumab) to 12.5% (with danvatirsen). For combination therapy with monalizumab, MPR was 30% and pCR was 10%.

The safety profile in the durvalumab monotherapy arm (treatment-related adverse events in 34.6% of patients) was similar to previously published data for anti-PD-1/PD-L1 antibodies. No new safety signals were identified with any of the combination regimens (treatment-related adverse events seen in 43.8% to 57.1% of patients).

MPR was associated with baseline tumor PD-L1 expression of ≥1% in the oleclumab and monalizumab combination arms. In the oleclumab (anti-CD73) combination arm, high baseline CD73 expression was associated with pathological tumor regression, and treatment decreased CD73 expression on tumor cells, as previously observed in other studies. The oleclumab combination also was associated with greater natural killer (NK) and CD8 T cell density in the tumor center on treatment compared with baseline, suggesting an increased infiltration of effector cells in the tumor microenvironment.

Updated translational studies on tumor tissues and blood samples revealed the impact of neoadjuvant treatment on the immune system. Transcriptome analysis on pre- and post-treatment samples showed an upregulation of genes associated with cytotoxicity, tertiary lymphoid structures and lymphocyte recruitment, all indicators of an activated immune response.   

The number of patients with no detected circulating tumor DNA (ctDNA) increased progressively from pre-to post-treatment and post-surgery follow up, highlighting the relationship between decreasing ctDNA levels and improved patient outcomes. Notably, surgery was the most effective intervention to result in clearance of ctDNA. Researchers also found an enrichment of beneficial bacteria in the gut microbiome of patients who achieved MPR. These bacteria were previously associated with a favorable immunotherapy response across several cancer types.

“Our study is a testament to how clinical trials designed with translational findings in mind can support the rapid advancement of novel immune-based combinations to larger scale studies,” Cascone said. “I’m encouraged by these early findings as we work toward reducing the risk of recurrence and increasing cure rates for patients with early-stage non-small cell lung cancer.” 

Limitations of the study include the exploratory nature of the endpoints, small sample sizes and investigator-assessed outcomes without central review.

Based on these results and the recent approval of neoadjuvant nivolumab plus chemotherapy, the team has launched a follow-up randomized clinical trial, NeoCOAST-2, with Cascone serving as the global principal investigator. The trial is now enrolling patients with resectable, stage IIA-IIIA NSCLC to receive neoadjuvant durvalumab combined with chemotherapy and either oleclumab or monalizumab, followed by surgery and adjuvant durvalumab plus oleclumab or monalizumab.

The study was funded by AstraZeneca, which developed durvalumab, oleclumab and monalizumab (with Innate Pharma). Cascone reports a consulting/advisory role and contracted institutional support/research consulting for MedImmune/AstraZeneca. A full list of co-authors and disclosures can be found here.