Margetuximab bests trastuzumab in advanced breast cancer

Adding margetuximab – a novel chimeric Fc-engineered anti-ERBB2* antibody – to single-agent chemotherapy (CT) yielded better survival benefit and favourable safety compared with the trastuzumab-CT regimen for women with pretreated ERRB2-positive advanced breast cancer (ERRB2+ ABC), according to the initial results of the phase III SOPHIA trial.

“ERRB2+ ABC remains typically incurable with optimal treatment undefined in later lines of therapy,” said the researchers. Treatment alternatives include neratinib, trastuzumab deruxtecan, and tucatinib; however, these apparently have ‘notable toxic effects’, they added. “Margetuximab may have a role for patients in this setting who are unable or unwilling to tolerate the toxic effects of these novel therapies.”

A total of 536 ABC patients (median age 56 years) with disease progression despite ≥2 prior anti-ERBB2 therapies** and 1–3 lines of nonhormonal therapy for metastatic BC were evaluated. After selecting the type of CT***, participants were randomized 1:1 to receive IV margetuximab 15 mg/kg (median six cycles) or trastuzumab 6 mg/kg (loading dose 8 mg/kg; median five cycles) on day 1 of each 3-week cycle, on top of the chosen CT. [JAMA Oncol 2021;doi:10.1001/jamaoncol.2020.7932]

Central blinded analysis revealed a longer progression-free survival (PFS) with margetuximab vs trastuzumab (median, 5.8 vs 4.9 months; hazard ratio [HR], 0.76; p=0.03), thus meeting the primary endpoint.

Investigator-assessed PFS also favoured margetuximab over trastuzumab, both in the primary (median, 5.6 vs 4.2 months) and second interim analyses (median, 5.7 vs 4.4 months), yielding significant reductions in the hazards of progression (HR, 0.70; p=0.001 [primary] and HR, 0.71; p<0.001 [interim]).

Centrally assessed objective response and clinical benefit rates (ORR and CBR, respectively) were also higher with margetuximab vs trastuzumab (22 percent vs 16 percent; p=0.06 [ORR] and 37 percent vs 25 percent; p=0.003 [CBR]). Investigator assessment generated similar findings (25 percent vs 14 percent; p<0.001 and 48 percent vs 36 percent; p=0.003, respectively).

Regardless of causality, the most common adverse events (AEs; occurring in ≥20 percent of patients) in both arms were fatigue, nausea, and diarrhoea. Vomiting was also typical with margetuximab. Discontinuation rates owing to AEs were similar between the margetuximab and trastuzumab arms (3.0 percent vs 2.6 percent).

One of the AEs of special interest (AESI) was infusion-related reactions (IRRs). Despite the higher incidence of all-grade IRRs with margetuximab vs trastuzumab (13 percent vs 3 percent), most were grade 1/2, occurred during the first infusion only, and resolved within 24 hours. Of the four margetuximab recipients with grade 3 IRRs, two discontinued treatment; the other two continued the regimen (≥5 cycles).

Another AESI observed in both arms was left ventricular (LV) dysfunction (n=7 in each arm), four of which were grade 3 (n=3 and 1 in the margetuximab and trastuzumab arms, respectively). LV ejection fraction (EF) monitoring led to dose delays or discontinuations (n=4 and 6, respectively). “[Nonetheless,] all LVEF reductions detected by monitoring were asymptomatic. [LVEF] reductions … were reversible for all patients with complete follow-up,” said the researchers.

Although margetuximab and trastuzumab share ERBB2 specificity, the former incorporates an engineered Fc region to boost immune activation, they noted. “[Taken together, our results show that] margetuximab-CT had acceptable safety … and a small but statistically significant PFS benefit compared with trastuzumab-CT in [this patient setting].”

Despite the similar overall survival (OS) rates between the margetuximab and trastuzumab arms during the second interim analysis (median, 21.6 vs 19.8 months; HR, 0.89; p=0.33), no definitive conclusions can be drawn owing to immature data. Final OS analysis is anticipated in 2021 (after 385 deaths).

A study comparing margetuximab and trastuzumab in patients with the low-affinity CD16A genotype is underway. “Immune-mediated therapies such as margetuximab may be more effective in the earlier disease setting where the immune system is relatively intact,” they added.