Exploring metastatic breast cancer immunotherapies: Are ADCs and ICIs the answer?

Breast cancer is the most common malignancy in women and the second most common cancer worldwide.¹ Rates of breast cancer are increasing in many parts of the world, reflecting its association with social and lifestyle factors related to economic development, as well as increases in life expectancy.²

Although the disease continues to increase in frequency, great strides have been made in treatment options and therefore in prognosis. In 40 years, the 10-year survival rate for breast cancer has almost doubled, from 40% in 1971 to 78% in 2011.³

Despite this, many continue to die from the disease because, while early-stage breast cancer is curable in 70%-80% of patients, metastatic breast cancer remains incurable.² In 2021, over 43,000 women and more than 500 men are expected to lose their lives from breast cancer in the U.S.⁴

What is metastatic breast cancer?

Breast cancer is considered metastatic when it has spread to other parts of the body. It is an invasive, stage 4 breast cancer type. Metastatic breast cancer indications include the presence of cancer cells in the circulatory or lymph system and/or in other organs such as bone, liver, or brain, and may be manifested in symptoms such as seizures, nausea, vomiting, jaundice, back pain, itchy skin and rash, abdominal discomfort and appetite loss.

There is an urgent need for new and more targeted treatments. Additional research into the molecular biology of the disease is generating a range of next-generation therapeutics, many of which are active via the immune system.

“Antibody-drug conjugates and immune checkpoint inhibitors may help improve the body’s immune response to breast cancer. “

Antibody-drug conjugates (ADCs) target cancer cells with cytotoxicity

Antibody-drug conjugates (ADCs) are a targeted form of treatment for cancer, designed to identify and kill cancer cells while sparing healthy tissue. They contain a monoclonal antibody targeted against a cancer cell-specific receptor connected to a cytotoxic drug. The ADC binds to an antigen found on the surface of the cancer cell which limits exposure of the other cells to the toxic compound, and therefore reduces off-target toxicity. The first ADC was approved in the U.S. in 2001.

ADCs are being developed for the treatment of HER2-positive breast cancer as well as triple-negative breast cancer (TNBC). TNBC describes breast cancer types that lack expression of the HER2 protein as well as estrogen and progesterone hormone receptors.

Immune checkpoint inhibitors (ICIs) are a type of immunotherapy that block inhibitory checkpoints in the immune system, allowing immune cells to continue to recognize and destroy cancer cells. The first ICI was approved in the U.S. in 2011.

ADCs and ICIs: A powerful combination

Together, ADCs and ICIs act to enhance the treatment effect. As of November 2020, the U.S. Food and Drug Administration has approved three ADCs and two ICIs for patients with metastatic breast cancer, which has no known cure to date. However, combination therapies have the potential for enhanced clinical efficacy and improved clinical outcomes in this patient population.⁵

ICIs boost the body’s immune response against cancer cells

ICIs are a mainstay of metastatic cancer immunotherapies. Their efficacy lies in their ability to restore the immune response against cancer. By blocking immune checkpoints—key regulators of the immune system that can dampen the immune response when stimulated by cancer cells—ICIs allow the immune system to continue fighting cancer cells. Today, they are the most promising clinical option to reverse tumor-mediated immune suppression in breast cancer and the U.S. Food and Drug Administration has approved two ICIs for this purpose.

When used in combination with chemotherapy, ICIs have shown particularly promising results in patients with metastatic TNBC, which currently has limited treatment options.

There are several ICIs in clinical development and research is ongoing to combine two ICIs into one treatment regimen, known as a dual ICI blockade. While primarily used for metastatic TNBC at present, as development continues, ICIs are likely to become part of the treatment regimen for other breast cancer subtypes.

The promise of dual therapy

ADCs and ICIs show impressive clinical results on their own but can also be combined for an enhanced effect.

“The combined use of ADCs and ICIs may be especially beneficial in patients with metastatic breast cancer whose disease has progressed following an initial response to therapies, and there is growing evidence to suggest that combining ADCs and ICIs could help overcome resistance to treatment.”

However, not all trials and not all patients have shown clinical benefit, highlighting the importance of patient selection and stratification. To obtain the optimum benefit from these targeted therapies, sponsors should adopt:

• A robust selection procedure using specific biomarkers
• A carefully reviewed dosing strategy. Any potential clinical benefit from an increased dosage may be offset by increases in toxicity, and it is important to be aware that, compared to chemotherapy agents, ICIs may have delayed and prolonged toxicity⁵

Although combined toxicity has also been a concern, data so far does not suggest significant additive toxicity from the combined use of ADCs and ICIs. ADCs and ICIs are also generally better tolerated than traditional chemotherapy.

Combined use of ADCs and ICIs shows promise as a metastatic breast cancer treatment

ADCs and ICIs are next-generation, targeted treatments for metastatic breast cancer that show impressive clinical efficacy independently and, when combined, act synergistically.

Multiple trials of dual therapy are underway, and initial results suggest that dual therapy could be clinically beneficial for patients with metastatic breast cancer whose disease may have progressed despite an initial response to treatment.

Looking ahead

There are several new compounds in development that could improve outcomes for patients with metastatic breast cancer and, potentially, early breast cancer too. In addition, research aims to enhance the synergistic action between ADCs and ICIs and improve their risk-to-benefit ratio. Improving the specificity and efficacy of the drug delivery of ADCs, for example, may reduce their toxicity and enhance their effect on ICIs.

Efforts are also underway to combine the properties of both ADCs and ICIs into a single compound: an immune-stimulating antibody conjugate. Studies in mice have shown a robust anti-tumor immune response from such a compound, with clinical trials underway and results eagerly awaited.

In a clinical trial setting, profiling patients through biomarker assays and delivering dual ADC-ICI therapy where appropriate could give a trial the best chance of success, thus giving a drug the best chance of approval. It also gives patients the best chance of survival—the ultimate goal of any treatment endeavor. With an estimated 284,200 new cases of breast cancer in the U.S. in 2021, ADC-ICI therapy offers a new treatment paradigm and fresh hope.