Optimized Therapy Requires More Than Binary Understanding of HER2 Positivity in Metastatic Breast Cancer

Komal Jhaveri, MD, FACP

Neratinib (Nerlynx)-based combinations, antibody-drug conjugates (ADCs), and bispecific antibodies represent novel and effective treatment options for patients with pretreated HER2-mutant and HER2-low metastatic breast cancer, but the successful integration of these regimens into care will require further investigation into current definitions of HER2 positivity, explained Komal Jhaveri, MD, FACP, in a presentation at the 21st Annual International Congress on the Future of Breast Cancer^® East.¹

Tapping Into the Power of Targeted Therapy

Triplet regimens with neratinib have demonstrated encouraging clinical activity in patients with HER2-mutant metastatic breast cancer; the success of these combinations trace back to initial demonstrations of neratinib’s preclinical efficacy in HER2-mutant patient-derived xenograft models and subsequent clinical efficacy in the SUMMIT trial (NCT01953926).² The study showed that single-agent neratinib elicited an objective response rate of 17% in patients with hormone receptor–positive disease (n = 18) and 20% in those with triple-negative disease (n = 10).

“To tackle the detrimental impact of the HER2 [and] ER crosstalk, it was important to add antiestrogen therapy to neratinib, at least for the hormone receptor–positive cohort, and this is what was done within multiple trials—including the SUMMIT cohort [in which] fulvestrant [Faslodex] was added to neratinib,” Jhaveri, associate attending in the Breast Medicine and Early Drug Development Service, section head of the Endocrine Therapy Research Program, and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, said in his presentation. The combination, which was administered to 39 patients, resulted in an increased ORR of 30.8% with a median duration of response (DOR) of 9.2 months.

Simultaneous work had shown that the combination of neratinib and trastuzumab (Herceptin) was superior to either agent alone in preclinical models, prompting SUMMIT investigators to further amend the trial to evaluate the triplet regimen of neratinib, fulvestrant, and trastuzumab, according to Jhaveri, who is also an assistant professor at Weill Cornell Medical College. Within the hormone receptor–positive cohort, the ORR was 35.3% with the triplet, and responses were seen regardless of histology, HER2 mutation or co-occurring HER3 mutation, and HER2 expression level by immunohistochemistry (IHC).³ Additionally, the triplet also prolonged median DOR to 14.3 months (95% CI, 6.4–not evaluable).

Although loperamide prophylaxis was mandated, diarrhea was the most common adverse effect reported with the triplet (any grade, 90.2%; grade 3, 51.0%), followed by expected events of nausea (any grade, 72.5%; grade 3, 3.9%), vomiting (any grade, 52.9%; grade 3, 7.8%), and fatigue (any grade, 43.1%; grade 3, 5.9%).

Within the triple-negative cohort, in which only the combination of neratinib and trastuzumab was administered, the ORR was 33.3%, with a median DOR that was NE. In this group, the most common AEs were diarrhea (any grade, 88.9%; grade 3/4, 16.7%), nausea (any grade, 50.0%, grade 3/4, 5.6%), vomiting (any grade, 50.0%; grade 3/4, 5.6%), and constipation (any grade, 38.9%; grade 3/4, 0%).

In addition to neratinib-based combinations, Jhaveri highlighted ongoing research for HER2-mutant metastatic breast cancer, including a phase 2 basket study (NCT04579380) evaluating the combination of tucatinib (Tukysa) and trastuzumab and the phase 1/2 MasterKey-01 trial (NCT04209465) evaluating BDTX0819, a potent and selective inhibitor of the allosteric oncogenic ErbB family.

Advancing the Paradigm With ADCs

ADCs have also garnered interest in HER2-mutant disease, owing in part to research from Memorial Sloan Kettering Cancer Center which showed an ORR of 44% with ado-trastuzumab emtansine (Kadcyla) in HER2-mutant lung cancer (n = 18), Jhaveri said.⁴ Subsequent work with fam-trastuzumab deruxtecan-nxki (Enhertu), now published in the New England Journal of Medicine, demonstrated an ORR of 55% with the ADC, as well as a median progression-free survival (PFS) of 8.2 months (95% CI, 6.0-11.9) and a median overall survival (OS) of 17.8 months (95% CI, 13.8-22.1).⁵

“We now eagerly await data from the phase 2 DESTINY-PanTumor01 study [NCT04639219], which is evaluating trastuzumab deruxtecan in various HER2-mutant solid tumors, including breast cancer, and another ADC, ARX788, is also being evaluated for HER2-mutated or HER2-amplified solid tumors,” Jhaveri said.

ADCs have also become important in HER2-low disease, which has historically been classified as HER2 negative with standard IHC and fluorescence in situ hybridization (FISH) assays, explained Jhaveri.

“When we traditionally think about HER2-positive disease, we were thinking about a binary way of thinking. We were thinking about HER2-positive and HER2-negative tumors, HER2-positive being defined as HER2 3+ with IHC or HER2 2+ with IHC, which is FISH amplified,” Jhaveri explained. “HER2 2+ that is not amplified or HER2 1+ and 0 are HER2 negative, but HER2-low is HER2 IHC 1+ or HER2 IHC 2+ that is not amplified.”

Early work demonstrating the efficacy of ADCs in this population demonstrated a notable ORR of 37.0% (95% CI, 24.3%-51.3%) and median PFS of 11.1 months with trastuzumab deruxtecan in a phase 1b trial in heavily pretreated patients with HER2-low advanced breast cancer.⁶

This trial set the stage for the phase 3 DESTINY-Breast04 trial (NCT03734029), in which patients with HER2-low unresectable or metastatic breast cancer were randomized to trastuzumab deruxtecan (n = 373) or physician’s choice of treatment (n = 184).⁷

Regarding notable patient characteristics, Jhaveri stated that 60% of patients had HER2 1+ and 40% had HER2 2+ with negative in situ hybridization; 90% had hormone receptor–positive disease (n = 499) and 10% had triple-negative disease (n = 58). Patients had received a median of 2 prior lines of endocrine therapy and 1 prior line of chemotherapy, and 70% of the hormone receptor–positive cohort had received prior CDK4/6 inhibition.

A “remarkable” median PFS of 10.1 months was observed with trastuzumab deruxtecan vs 5.4 months with physician’s choice in the hormone receptor–positive cohort, meeting the primary end point of the study (HR, 0.51; 95% CI, 0.40-0.64; P < .001). Similar results were seen in the overall population, with a median PFS of 9.9 months and 5.1 months, respectively (HR, 0.50; 95% CI, 0.40-0.63; P < .001). 

Additionally, a statistically significant improvement in OS was reported in the HR-positive (HR, 0.64; 95% CI, 0.48-0.86; P = .003) and all-comer population (HR, 0.64; 95% CI, 0.49-0.84; P = .001).

Furthermore, a subgroup analysis of the hormone receptor–positive population illustrated that the PFS benefit was maintained with trastuzumab deruxtecan, regardless of prior CDK4/6 inhibition, IHC status, and prior number of lines of chemotherapy.

Similar improvements were noted in the exploratory analyses done in the hormone receptor–negative, HER2-low population, which comprised 58 patients. “Despite small numbers, we see this unprecedented and very impressive data, where there is a statistically significant improvement in PFS [HR, 0.46; 95% CI, 0.24-0.89] and OS [HR, 0.48; 95% CI, 0.24-0.95],” Jhaveri said.

In terms of safety, the most common AEs were in line with what has been reported in previous trials examining the ADC, and included nausea (any grade, 73%; grade >3, 5%) and neutropenia (any grade, 33%, grade ≥3, 14%). Additionally, drug-related interstitial lung disease/pneumonitis occurred in 12.1% of patients in the trastuzumab deruxtecan arm, and resulted in 3 deaths.

“[Trastuzumab deruxtecan] is going to be a new standard that we will be using for our patients in clinic if they’ve had up to 2 lines of chemotherapy,” Jhaveri said. “The next step here is the DESTINY-Breast06 [NCT04494425], in which we’re trying to see whether this agent would be appropriate even earlier in the metastatic setting, in a chemotherapy-naïve patient population.”

Additional trials of interest include the phase 2 TRIO-US B-12 TALENT trial (NCT04553770), which is evaluating the ADC in the neoadjuvant setting, as well as the phase 1 DESTINY-Breast08 trial (NCT04556773) and the phase 1/2 BEGONIA trial (NCT03742102), which are evaluating the agent in potential combination regimens.

Apart from trastuzumab deruxtecan, other ADCs, including trastuzumab duocarmazine (SYD985) and disitamab vedotin (RC48), are also under exploration in patients with HER2-low metastatic breast cancer have shown preliminary response rates of 32% and 40%, respectively.^8,9

“Both agents are being evaluated further with combinations,” Jhaveri said. “Trastuzumab duocarmazine is being evaluated in combination with paclitaxel, both in the metastatic setting and within the I-SPY trial [NCT01042379] in the neoadjuvant setting. Another important combination that is being studied is trastuzumab duocarmazine with niraparib [Zejula], a PARP inhibitor, and disitamab vedotin is being evaluated in randomized registration phase 3 trial where we’re looking at the agent vs physician’s choice chemotherapy.”

Additional agents of interest include the HER2/HER3-directed bispecific antibody, zenocutuzumab (MCLA-128), which demonstrated a clinical benefit rate of 16.7% in combination with endocrine therapy in pretreated patients with hormone receptor–positive, HER2-low metastatic breast cancer.¹⁰

Confronting Current Challenges With HER2-Low Testing

Now that the field is moving away from a binary understanding of HER2 expression, however, investigators will need to address the challenges of current HER2 testing platforms in the clinic to identify patients with HER2-low disease, Jhaveri explained.

“IHC [platforms were] not developed to detect HER2 and HER2 1+,” Jhaveri said. “They were optimized to detect HER2 3+ or HER2 amplified tumors.”

In a study, 18 experienced pathologists were asked to rescore HER2 on selected breast cancer slides, and only 26% concordance was seen between HER2 IHC 0 and 1+ scores.¹¹

“We’re going to need quantitative biomarkers and artificial intelligence applied to digital pathology to address this unmet need of how we think about HER2-unamplified tumors,” Jhaveri concluded.

References

1. Jhaveri K. What’s new for HER2-mutant and HER2-low metastatic breast cancers. Presented at: 21st Annual International Congress on the Future of Breast Cancer^® East: July 15-16, 2022; New York, NY.
2. Jhaveri K, Haeseong P, Waisman J, et al. Neratinib + fulvestrant + trastuzumab for hormone-receptor positive, HER2-mutant metastatic breast cancer, and neratinib + trastuzumab for HER2-mutant metastatic triple-negative disease: latest updates from the SUMMIT trial. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS4-10.
3. Jhaveri KL, Goldman JW, Hurvitz SA, et al. Neratinib plus fulvestrant plus trastuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial. J Clin Oncol. 2022;40(suppl 16):1028. doi:10.1200/JCO.2022.40.16_suppl.1028
4. Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol. 2018;36(24):2532-2537. doi:10.1200/JCO.2018.77.9777
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6. Modi S, Park H, Murthy RK, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol. 2020;38(17):1887-1896. doi:10.1200/JCO.19.02318
7. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
8. Banerji U, van Herpen CML, Saura C, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20(8):1124-1135. doi:10.1016/S1470-2045(19)30328-6
9. Wang J, Liu Y, Zhang Q, et al. RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: A pooled analysis of two studies. J Clin Oncol. 2021;39(suppl 15):1022. doi:10.1200/JCO.2021.39.15_suppl.1022
10. Pistilli B, Wildiers H, Hamilton EP, et al. Clinical activity of MCLA-128 (zenocutuzumab) in combination with endocrine therapy (ET) in ER+/HER2-low, non-amplified metastatic breast cancer (MBC) patients (pts) with ET-resistant disease who had progressed on a CDK4/6 inhibitor (CDK4/6i) J Clin Oncol. 2020;38(suppl 15):1037. doi:10.1200/JCO.2020.38.15_suppl.1037
11. Fernandez AI, Liu M, Bellizzi A, et al. Examination of low ERBB2 protein expression in breast cancer tissue. JAMA Oncol. 2022;8(4):1-4. doi:10.1001/jamaoncol.2021.7239