Although it has been difficult to identify a specific target for triple-negative breast cancer, several therapeutic classes are showing great promise.
Stephanie LaBomascus, MD
Triple-negative breast cancer (TNBC) is a heterogenous disease that is diagnosed in the absence of HER2 and hormone receptors. Though it has been difficult to identify a specific target for such a heterogenous disease, several therapeutic classes are showing great promise.
“Molecular profiling has revealed an unexpectedly high amount of heterogeneity as well as some common features within TNBC,” said Stephanie LaBomascus, MD, in a presentation during the 2019 OncLive® State of the Science Summit™ on Breast Cancer.
“It’s unlikely we’re going to find a one-size-fits-all approach,” she added. “Understanding the fundamental differences in these tumors, and their biology is the first step in the development of targeted therapies for these patients.”
At the meeting, LaBomascus, a fellow at Rush University Medical Center, discussed the headway that is being made among the 3 most promising therapeutic classes: immunotherapy, PARP inhibitors, and antibody-drug conjugates (ADCs).Of all of the breast cancer subtypes, TNBC has the most robust tumor infiltrate. As such, elevated levels of tumor infiltrating lymphocytes can enable an immune response and lead to improved outcomes. However, a key component of unmasking tumor cells to the immune system is inhibition of the PD-1/PD-L1 pathway, which can restore antitumor T-cell activity, said LaBomascus.
“TNBC tends to have a higher genomic instability and higher mutational burden, which translates to a higher propensity to generate neoantigens that stimulate the immune system,” said LaBomascus.
Though initial trials with pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq) showed modest activity and durable responses as single agents in TNBC, it was not enough to warrant further exploration as monotherapy. Thus, after extrapolating data from other cancers, immunotherapy was combined with chemotherapy in the landmark phase III IMpassion130 trial.1
In the trial, patients were randomized to 840 mg of atezolizumab on days 1 and 15 of every 28-day cycle and 100 mg/m2 of nab-paclitaxel (Abraxane) on days 1, 8, and 15 of every 28-day cycle (n = 451), or placebo on the same schedule as atezolizumab and nab-paclitaxel (n = 451). Eligibility criteria included a diagnosis of metastatic or inoperable locally advanced TNBC, no prior therapy for advanced disease, and an ECOG performance status ≤1. Prior taxane use ≥12 months was allowed, noted LaBomascus.
Progression-free survival (PFS) and overall survival (OS) among the intent-to-treat (ITT) and
PD-L1—positive cohorts served as coprimary endpoints of the trial, where a PD-L1 staining >1% equated to positivity, said LaBomascus.
The immunotherapy and placebo arms demonstrated similar rates of median PFS in the ITT population (7.2 vs 5.5 months; HR, 0.80) and the PD-L1—positive group (7.5 vs 5.0 months; HR, 0.62), respectively. Median OS in the ITT (21.3 vs 17.6 months; HR, 0.84) and PD-L1–positive group (25.0 vs 15.5 months; HR, 0.62) favored the immunotherapy combination in both subsets. Moreover, the 2-year OS was 54% among patients who received the immunotherapy combination versus 37% with placebo.
PD-L1—negative patients withstanding, all patients, irrespective of the number of liver, brain, or lung metastases, prior taxane use, age, ECOG performance status, and prior neoadjuvant chemotherapy derived a benefit with the immunotherapy combination.
Adverse events (AEs) were consistent with the agent’s known safety profile, leading to the regimen’s accelerated FDA approval for patients with unresectable or metastatic PD-L1—positive TNBC in March 2019 in conjunction with the Ventana PD-L1 assay used in the trial.
“We recently saw the first approval for immunotherapy in breast cancer, and I for one am very hopeful that this is just a taste of what’s to come in improving outcomes for these patients,” said LaBomascus.Patients who express BRCA1/2 mutations are predisposed to DNA double-stranded breaks by the homologous recombination repair pathway, explained LaBomascus. By introducing PARP enzymes, repair of DNA single stranded breaks is possible, she added.
As it stands, olaparib (Lynparza) and talazoparib (Talzenna) are the only FDA-approved PARP inhibitors for patients with germline BRCA (gBRCA)-mutated breast cancer.
Olaparib’s approval came following the results of the phase III OlympiAD trial, in which patients with estrogen or progesterone receptor—positive, HER2-negative or triple-negative disease with a deleterious gBRCA mutation and ≤2 prior lines of chemotherapy were randomized 2:1 to 300 mg of olaparib (n = 205) twice daily or physician’s choice chemotherapy (n = 97). Patients were well balanced between treatment arms, said LaBomascus.
Per the study’s primary endpoint, PFS was 7.0 months in the olaparib arm and 4.2 months in the placebo arm (HR, 0.58; 95% CI, 0.43-0.80; P <.001).2 Moreover, response rates were 59.9% with olaparib versus 28.8% with placebo. This benefit was higher among patients with chemotherapy-naïve TNBC in the metastatic setting, added LaBomascus.
Tolerability with olaparib was comparable with chemotherapy, apart from anemia which was significantly higher in the olaparib arm and neutropenia, which was higher in the chemotherapy arm.
Olaparib is also being investigated in combination with neoadjuvant platinum-based chemotherapy in women with basal-like TNBC or gBRCA-mutant disease in the ongoing phase III PARTNER trial (NCT03150576), said LaBomascus.
“The rationale behind the study surrounds the idea that these basal-like breast cancers have a homologous recombination deficiency similar to the biology we see in gBRCA-mutated patients. Carboplatin-based chemotherapy will induce DNA damage, and the addition of a PARP inhibitor is thought to increase that synthetic lethality,” said LaBomascus.
Whether or not a high potency PARP inhibitor is able to compound the efficacy of an already effective platinum agent remains to be seen, noted LaBomascus.
The phase III EMRACA trial was similarly designed by randomizing patients 2:1 to 1 mg of talazoparib (n = 287) once daily or physician’s choice chemotherapy (n=144). As in the OlympiAD trial, approximately half of patients had TNBC. However, a higher percentage of patients in the talazoparib arm had more aggressive disease, quantified by a <12-month disease-free interval from the time of initial diagnosis to advanced disease. The majority of patients had only been exposed to ≤1 prior line of chemotherapy, said LaBomascus.
The experimental and placebo arms resulted in slightly superior rates of median PFS than in the OlympiAD trial, at 8.6 months and 5.6 months, respectively (HR, 0.54; 95% CI, 0.41-0.71; P <.001). However, response rates were consistent with what was observed in the OlympiAD trial, at 62.6% and 27.2%.
For those who are both PD-L1—positive and germline BRCA1/2 mutated disease, the question of whether to start with immunotherapy or a PARP inhibitor remains unclear, said LaBomascus.
However, several trials are exploring a combination of PARP inhibitors and immunotherapy as a potential treatment strategy, including the MEDIOLA, DORA, and TOPACIO trials, added LaBomascus. In TOPACIO, patients were randomized to 200 mg of niraparib and 200 mg of pembrolizumab on day 1 of every 21-day cycle. Preliminary data demonstrated an objective response to the combination irrespective of PD-L1 and BRCA status. Although, the ORR among PD-L1—positive patients was more than double that of PD-L1–negative patients.
Notably, the ORR among the triple-negative, BRCA-mutant cohort was similar to that of PARP monotherapy trials, suggesting the addition of immunotherapy did not add a significant increase in response, said LaBomascus.Unlike checkpoint inhibitors, ADCs are thought to deliver drugs directly to the cellular tissue and increase the potency of drug while minimizing the side effects, said LaBomascus. By linking cytotoxic agents to selective monoclonal antibodies through a linker protein, these drugs can travel to the intended tumor cell and induce cell death once internalized.
Two of the most promising compounds in development are sacituzumab govitecan and ladiratuzumab vedotin, said LaBomascus. Sacituzumab govitecan is an ADC of the chemotherapy metabolite SN-38, which is the active metabolite of irinotecan. It’s attached to the humanized IgG antibody targeting TROP-2, a glycoprotein found on >90% of TNBC tumors with a capacity to deliver 7.5 times more cytotoxic drug than can be delivered systemically, said LaBomascus.
Data from the 2017 San Antonio Breast Cancer Symposium indicated an ORR of 35% in heavily pretreated patients and a median PFS of 5.5 months compared with historical rates of 2 to 3 months with chemotherapy, said LaBomascus. Now, the agent is being compared with physician’s choice chemotherapy in the phase III ASCENT trial (NCT02574455) in patients with relapsed/refractory disease after having received ≥2 prior lines of chemotherapy for advanced disease. Although, the drug was granted a priority review designation by the FDA in July 2018, it has been flagged for further review before it can be brought to market, said LaBomascus.
Finally, ladiratuzumab vedotin is an ADC that combines the microtubule disrupting agent, monomethyl auristatin E with a humanized antibody conjugated through a proteolytically cleavable linker to the zinc transporter LIV-1, a protein commonly upregulated in TNBC. Similarly to sacituzumab govitecan, the ADC shows an ORR around 37%. Ongoing studies are examining the agent as monotherapy (NCT03424005) and in combination with immunotherapy (NCT03310957), said LaBomascus.