ADCs With Non-Cytotoxic Payloads May Represent the Future of HER2+ Breast Cancer Treatment

Mark Pegram, MD

The emergence of novel agents like fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib (Tukysa) in the HER2-positive breast cancer treatment paradigm have served to markedly improve outcomes for those with this disease, according to Mark Pegram, MD, who added that the future looks bright. Efforts are underway to develop antibody-drug conjugates (ADCs) with non-cytotoxic payloads, further investigate antibody fusions, and determine ways to enhance antibody-dependent cellular phagocytosis (ADCP) to further move the needle forward.

“Trastuzumab [Herceptin] remains the backbone of therapy…ado-trastuzumab emtansine (T-DM1; Kadcyla) is still available and is still being used, [although we] need to understand its activity following trastuzumab deruxtecan and post tucatinib,” Pegram said. “[We have seen] extraordinary activity with trastuzumab deruxtecan, including in the central nervous system [CNS] and in HER2-low [disease. Tucatinib has level 1 evidence of an overall survival [OS] benefit, including in those with brain metastases. Future directions will include ADCs with non-cytotoxic payloads.”

In a presentation delivered during the 21st Annual International Congress on the Future of Breast Cancer® (IBC) East, Pegram, who is the Susy Yuan-Huey Hung Professor of Oncology, medical director of the Clinical and Translational Research Unit, and associate dean for Clinical Research Quality at Stanford University School of Medicine, discussed the discovery of HER2 as a target in this disease, challenges faced with early clinical development, recent treatment advances, and emerging approaches that are generating excitement.

The Challenge of Early Clinical Development

“[In the 90s,] we didn’t know much about the target. We had no structural information about HER2; it was an orphan receptor. We assumed it had a ligand; it turns out it does not. We didn’t know the mechanism of action of these antibodies,” Pegram said. “We presumed it blocked the ligand, and that was wrong. We didn’t know the dose to use, we didn’t know the schedule, and we didn’t know what to expect [with regard] to safety.”

Pegram added that it was unclear whether that kind of antibody should be given alone or whether it should be used in combination with other agents like chemotherapy, endocrine therapy, or both. Investigators did not know what clinical setting to use it in, what disease to use it in, what stage of disease, or what the duration of therapy should be, according to Pegram.

Due to the difficulties in characterizing HER2, all the trials that were conducted early on included HER2 immunohistochemistry (IHC) of 2+ as eligibility criteria because investigators did not know what the cutoff was for response to the antibodies under exploration, Pegram said. Ultimately, HER2 IHC of 3+ was selected.

“Back in those days, they didn’t know how to describe this continuous variable, because HER2 can be expressed at many different levels. And so, they just made up a scale of [HER2 IHC] 1+, 2+, and 3+, that was rather arbitrary,” Pegram explained. “They had no idea that would become a clinical determinant of patient selection when they did that.”

Trastuzumab emerged as the first biologic therapy in breast cancer, according to Pegram. Since 1998, Pegram estimated that more than 2.5 million women with HER2-positive disease worldwide have received the agent as part of their treatment journey. The agent continues to be the backbone of therapy in early- and late-stage disease, according to Pegram, who added that it also served as a platform for antibody engineering, such as the advent of ADCs.

ADCs Shake Up the Space

“We had hoped that the antibodies themselves would be [our] magic bullet. We were frustrated when all our efforts in the 1990s and 2000s resulted merely in combinations of chemotherapy with HER2 antibodies…[where patients] still suffered from the [adverse] effects of chemotherapy,” Pegram said. “Our collaborators…came to the rescue with the advent of ADCs. [These agents are] kind of the best of both worlds; you get an antibody, you get the payload, and it’s directed, so hopefully, the toxicity is less than the free payload.”

T-DM1

Data from the phase 3 EMILIA trial (NCT00829166), which randomly assigned 991 patients with HER2-positive breast cancer who had received prior trastuzumab and a taxane to either T-DM1 (n = 495) or lapatinib (Tykerb) plus capecitabine (Xeloda; n = 496), showed that the median progression-free survival (PFS) with the ADC was 9.6 months vs 6.4 months with lapatinib plus capecitabine (HR, 0.65; 95% CI, 0.55-0.77; P < .001).² The median overall survival (OS) with T-DM1 was 30.9 months (95% CI, 26.8-34.3) vs 25.1 months (95% CI, 22.7-28.0) with the doublet (HR, 0.68; 95% CI, 0.55-0.85; P = .0006).³

“We don’t know how well this agent works after the likes of trastuzumab deruxtecan or after tucatinib; those data are still not available,” Pegram noted.

Trastuzumab Deruxtecan

The HER2-targeted ADC, trastuzumab deruxtecan, has a tumor-selectable cleavable linker and a high potency, membrane-permeable payload with a short systemic half-life. Notably, the agent also has a high drug:antibody radio of approximately 8. “The cleavable linker may be 1 major advantage over [other agents like] T-DM1, for example, as well as the bystander effect because it is a sizable payload,” Pegram explained.

The agent was examined in patients with unresectable or metastatic HER2-positive breast cancer who previously received trastuzumab and a taxane in the advanced or metastatic setting, as part of the pivotal phase 3 DESTINY-Breast03 trial (NCT03529110).⁴ Here, participants were randomized 1:1 to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 261) or T-DM1 (n = 263).

Data presented during the 2021 ESMO Congress showed that the median PFS with trastuzumab deruxtecan had not yet been reached (95% CI, 18.5–not estimable [NE]) vs 6.8 months (95% CI, 5.6-8.2) with T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10^-22). The 12-month PFS rates in the trastuzumab deruxtecan and T-DM1 arms were 75.8% (95% CI, 69.8%-80.7%) and 34.1% (95% CI, 27.7%-40.5%), respectively. The median OS was NE in both arms (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). The 12-month OS rates with trastuzumab deruxtecan and T-DM1 were 94.1% (95% CI, 90.3%-96.4%) and 85.9% (95% CI, 80.9%-89.7%), respectively.⁴

Moreover, the confirmed objective response rate (ORR) was also higher with trastuzumab deruxtecan vs T-DM1, at 79.7% (95% CI, 74.3%-84.4%) and 34.2% (95% CI, 28.5%-40.3%), respectively (P < .0001). Of those who responded to treatment with trastuzumab deruxtecan, 16.1% achieved a complete response (CR), and 63.6% experienced a partial response (PR).

“The ORR [with trastuzumab deruxtecan is] just astronomical…really dramatic efficacy signals here,” Pegram noted. Consistent benefit was observed with trastuzumab deruxtecan over T-DM1 across the key subgroups analyzed. “This is a biostatistian’s dream; there were no outliers here. We saw nothing crossing 1.0. Everyone is happy,” Pegram added.

DESTINY-Breast03 served as the confirmatory trial for the May 2022 FDA approval of trastuzumab deruxtecan for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti–HER2-based regimen in the metastatic setting or in the neoadjuvant or adjuvant setting and who have developed disease recurrence during or within 6 months of therapy completion.⁵

Trastuzumab deruxtecan was also found to have activity in patients with brain metastasesat baseline. At a median follow-up of 15.9 months, the median PFS was 15.0 months (95% CI, 12.5-22.2) with trastuzumab deruxtecan (n = 36) vs 3.0 months (95% CI, 2.8-5.8) with T-DM1 (n = 36; HR, 0.25; 95% CI, 0.13-0.45).⁶ The 12-month PFS rates in this subgroup were 72.0% (95% CI, 55.0%-83.5%) and 20.9% (95% CI, 8.7%-36.6%), respectively.

In those without baseline brain metastases, the median PFS with trastuzumab deruxtecan was NE (95% CI, 22.2-NE) vs 7.1 months (95% CI, 5.6-9.7) with T-DM1 (HR, 0.30; 95% CI, 0.22-0.40). The 12-month PFS rates were 76.5% (95% CI, 70.0%-81.8%) and 36.4% (95% CI, 29.4%-43.4%), respectively.⁶

Among those who received trastuzumab deruxtecan, 27.8% achieved an intracranial CR and 36.1% experienced a PR; these rates were 2.8% and 30.6%, respectively, for those who were given T-DM1.

“In terms of toxicities, patients on the study were on trastuzumab deruxtecan much longer than T-DM1, so they tended to accumulate an absolute number of more adverse effects because they were on the drug longer,” Pegram said. “If you adjust for time on drug, it turns out that there’s really parity or even benefit from trastuzumab deruxtecan in terms of safety when compared with T-DM1; that’s really quite striking.”

Pegram added that it is important to monitor for interstitial lung disease (ILD) in patients who are receiving trastuzumab deruxtecan. If this toxicity is suspected, the drug should be interrupted. “Consult with pulmonology, get a consultation, decide what workup to do, and then consider steroids if clinically indicated,” Pegram said.

Tucatinib Takes the Stage

The HER2-selective kinase inhibitor, tucatinib, was evaluated in combination with trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer who previously received treatment with trastuzumab, pertuzumab (Perjeta), and T-DM1, as part of the phase 2 HER2CLIMB trial (NCT02614794).⁷

Study participants were randomized 2:1 to tucatinib at 300 mg twice daily plus trastuzumab at 6 mg/kg every 3 weeks and capecitabine at 1000 mg/m² twice daily for days 1 through 14 (n = 410) or trastuzumab/capecitabine alone (n = 202). The tucatinib triplet resulted in a median PFS of 7.8 months (95% CI, 7.5-9.6) vs 5.6 months (95% CI, 4.2-7.1) with the doublet (HR, 0.54; 95% CI, 0.42-0.71; P < .001).⁷

Data from the trial supported the April 2020 FDA approval of tucatinib in combination with trastuzumab plus capecitabine in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, after at least 1 previous anti–HER2-based regimen in the metastatic setting.⁸

Notably, the tucatinib regimen (n = 198) also provided an OS benefit over trastuzumab plus capecitabine (n = 93) in those with brain metastases (HR, 0.58; 95% CI, 0.40-0.85; P = .005), translating to a 42% reduction in the risk of death.⁹ The median OS was 18.1 months (95% CI, 15.5-NE) with the triplet vs 12.0 months (95% CI, 11.2-15.2) with the doublet. The 1-year OS rates in the investigative and control arms were 70.1% (95% CI, 62.1%-76.7%) and 46.7% (95% CI, 33.9%-58.4%), respectively.

The addition of tucatinib to trastuzumab/capecitabine (n = 118) also provided an OS benefit over trastuzumab plus capecitabine (n = 56) in those with active brain metastases, at 20.7 months (95% CI, 15.1-NE) and 11.6 months (95% CI, 10.5-13.8), respectively (HR, 0.49; 95% CI, 0.30-0.80; P = .004). This was also true in those with stable brain metastases. In this subset, tucatinib plus trastuzumab/capecitabine (n = 80) resulted in a median OS of 15.7 months (95% CI, 13.8-NE) vs 13.6 months (95% CI, 10.2-22.0) with trastuzumab/capecitabine alone (HR, 0.88; 95% CI, 0.45-1.70; P = .70).⁹

Moreover, tucatinib plus trastuzumab and capecitabine (n = 80) resulted in a 69% reduction in the risk of CNS progression or death in those with stable brain metastases vs trastuzumab/capecitabine alone (n = 37; HR, 0.31; 95% CI, 0.14-0.67; P = .002).⁹

“The brain metastases data for tucatinib [were] really striking—even [those] with active brain metastases have an OS benefit with tucatinib when combined with capecitabine and trastuzumab,” Pegram said.

Future Directions: What’s Next?

BDC-1001 is a novel HER2-targeted antibody conjugate that is currently under exploration as a single agent and in combination with nivolumab (Opdivo) in patients with advanced HER2-expressing solid tumors in a phase 1/2 trial (NCT04278144).¹⁰ Specifically, the agent is comprised of an investigational trastuzumab biosimilar that is conjugated to a TLR7/8 agonist with a noncleavable linker. The agent was designed to stimulate the innate immune system, inducing antibody-mediated effector functions and a durable adaptive immune response.

“[This agent has] an immunologic payload instead of a cytotoxic payload,” Pegram noted. “We are [participating] in the phase 1 trial at our institution.”

Preliminary data showed that the agent had acceptable tolerability when evaluated at doses up to 5 mg/kg. Moreover, the agent was also found to have early clinical activity, including in those who received prior anti-HER2 therapy.

The STING pathway agonism has emerged as a potential approach to encourage antitumor immune responses, and it has been demonstrated that ADCs targeting tumor cells that carry a novel STING agonist can produce antitumor activity without significantly increasing systemic cytokine levels.¹¹ In a recent study, investigators evaluated the mechanism of FcγR-mediated internalization of these ADCs in myeloid cells. Compared with CD11b-targeted ADCs, cell–targeted ADCs resulted in a greater production of interferons and other cytokines and stronger cancer cell killing.

“[XMT-2056] will start first-in-human phase 1 studies this fall at our institution,” Pegram added.¹²

Another novel agent under investigation, CAT-01-106 is a trastuzumab-based ADC that is conjugated to maytansine through a noncleavable linker; this agent been shown to have a drug:antibody ratio of 1.8, which is about half the average ratio of T-DM1.¹³ The novel ADC demonstrated better in vivo efficacy than that of T-DM1 at equal payload dosing. Moreover, at equal payload dosing up to 120 mg/kg, CAT-01-106 was also found to have equal or better tolerability than T-DM1.

“[We’re also] looking at intracellular trafficking of ADCs and found a mechanism of resistance of T-DM1 is dysregulation of trafficking proteins between the endosome and the lysosome,” Pegram said. “That’s why I believe that these cleavable linkers are important because if you have a cleavable linker, you don’t need to go all the way to the lysosome, and that can be a big advantage.”

Another strategy under exploration is antibody-enzyme conjugates, which selectively remove sialic acids from cancer cells.¹⁴ The antibody directs the enzyme to the cancer cells and the enzyme cleaves the sugars. Subsequently, the antibody directs immune cells to eliminate desialylated cancer cells.

Pegram also shared efforts being made to combine CD47 blockade with trastuzumab to eliminate HER2-positive breast cancer cells as a way to overcome trastuzumab ADCC tolerance.¹⁵ Specifically, a study evaluated the combination of magrolimab with trastuzumab in HER2-positive breast cancer cells. The approach was found to have increased efficacy because of the macrophages, which strengthened antibody-dependent cellular phagocytosis—even when cancer cells were tolerant to trastuzumab-induced ADCC by natural killer cells.

“We would like to take that into a phase 1 study at our institution shortly,” Pegram concluded.

References

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