The ASCO 2016 Annual Meeting marks another year of progress in clinical cancer research. For breast cancer patients, pressing clinical issues such as the use of extended adjuvant hormonal therapy beyond 5 years, the role of anthracycline in the adjuvant setting for HER2-negative disease, utility of pertuzumab post progression on trastuzumab containing regimens and the potential of trastuzumab biosimilars for HER2-positive metastatic disease, and data further supporting the benefit of CDK4/6 inhibition and the prognostic and predictive value of ESR1 mutations in estrogen receptor positive (ER+) breast cancer were addressed at the meeting to better inform our decisions in the clinic.
In addition, novel therapeutic targets such as HER2 mutation in HER2 non-amplified breast cancer and glutaminase in triple negative breast cancer (TNBC) have shown promising results in early phase trials that warrant further investigation.
Abstract 505: Persistent risk of recurrence post 5 years of adjuvant endocrine therapy
EBCTCG meta-analysis that included 46,000 women with early stage ER+ breast cancer post 5 years of tamoxifen or aromatase inhibitor (AI) demonstrated that the risk of distant recurrence persists in subsequent years. Without extended endocrine therapy, distant recurrence risk in years 5-20 was approximately 14 percent for stage 1 disease and much greater for higher stage or node positive disease.
Abstract LBA1: Extending adjuvant AI beyond 5 years
MA 17.R was a double-blind, placebo-controlled phase III trial evaluating the efficacy of preventing breast cancer recurrence with 5 additional years of letrozole versus placebo in postmenopausal women with early stage ER+ breast cancer who already completed 5 years of adjuvant letrozole following 0-5 years of tamoxifen.
The primary endpoint was disease-free survival (DFS). The study enrolled 1,918 women (median follow-up: 6.3 years). Compared to placebo, letrozole led to 4 percent absolute improvement in 5-year DFS (95% vs 91%; HR 0.66; p=0.01), including 1.1 percent absolute risk reduction in distant recurrence rate (4.4% vs 5.5%), without substantive difference in quality of life assessed by MENQOL and SF-36. The benefit was independent of nodal status, prior adjuvant chemotherapy, time since the last dose of AI, and duration of prior tamoxifen. A large effect was observed in contralateral breast cancer incidence (1.4% vs 3.2%; HR 0.42, p=0.007). No difference in 5-year overall survival was observed (93% in the letrozole arm and 94% in the placebo arm; HR of 0.97 (p=0.83)). Letrozole was associated with increased incidence of bone fracture (14% vs 9%; p=0.001).
This data supports the use of extended AI therapy beyond 5 years in postmenopausal women in the adjuvant setting to reduce the risk of recurrence and preventing new primary breast cancer, with the caveats of increased bone fracture and the lack of overall survival benefit in unselected patient population. Tailored assessment of individual risk of recurrence is needed.
Abstract 507: Phase III confirmation of palbociclib benefit in combination with letrozole in postmenopausal women with ER+/HER2- advanced breast cancer
PALOMA 3 randomized 666 patients with advanced ER+/HER2- breast cancer to received either palbociclib/letrozole (n=444) or placebo/letrozole (n=222) as first line hormonal therapy. The addition of palbociclib led to a significant improvement in progression free survival (PFS): 24.8 (22.1-NR) months in the palbociclib/letrozole arm vs 14.5 (12.9-17.1) months in the placebo/letrozole arm, HR 0.58; p<0.000001. All subgroups derived benefit. Palbociclib was associated with an improved response rate (42% vs 35%, p=0.03) and clinical benefit rate (85% vs 70%, p<0.0001). The study provided confirmatory support for the indication of palbociclib plus letrozole as first line therapy for metastatic ER+HER2- breast cancer.
Abstract 510: Abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, demonstrated benefit for heavily pretreated advanced ER+HER2- breast cancer
MONARCH 1 is a single arm phase II trial of abemaciclib 200mg Q12h in patients with metastatic HR+HER2- breast cancer progressed on or after prior endocrine therapy and at least two chemotherapy regimens (at least 1 taxane regimen and 1 regimen in the metastatic setting). One hundred thirty two patients, a median of three prior systemic regimens for metastatic disease, enrolled to the study. The clinical benefit rate of 42.4 percent and overall response rate of 19.7 percent were observed, clearly indicating its activity in ER+ breast cancer. Most common adverse events were diarrhea (90.2%) (grade 1: 41.7%, grade 2: 28.8%, grade 3: 19.7%). Neutropenia (87.7%) (grade 1, 17.7%, grade 2: 43.1%, grade 3: 22.3%, grade 4: 4.6%) was less severe than other CDK4/6 inhibitors. The preferential effect on CDK4, daily dosing schedule, and the toxicity profile differentiate abemaciclib from other CDK4/6 inhibitors. Abemaciclib in combination with nonsteroidal AI as first line (MONARCH 3) and in combination with fulvestrant in endocrine pre-treated setting (MONARCH 2) are ongoing.
Abstracts 511 and 512: ESR1 mutation by ctDNA in MBC
In a retrospective study of ctDNA ESR1 mutation (D538G, Y537S/N/C) by digital droplet PCR at disease progression after first-line AI in patients with metastatic breast cancer, ESR1 mutation was detected in 44/144 (30.6%) patients and was a strong and independent prognostic factor for PFS to subsequent therapy and OS.
In the SoFEA study, ESR1 mutation was associated with worse PFS while on exemestane compared to fulvestrant, consistent with the preclinical data indicating that these mutations lead to estrogen independent ER activation. In the PALOMA-3 study, ctDNA ESR1 mutation was detected in 27 percent baseline samples by BEAMing digital PCR. Benefit of palbociclib was observed in both ESR1 mutated versus wild type cohorts.
Abstract 518: Efficacy of pan-HER inhibitor neratinib in HER2 mutated non-amplified MBC
Approximately 2 percent of HER2 non-amplified breast cancers harbor recurrent mutations in HER2. Results of a multi-center phase II trial of neratinib in HER2 mutated non-amplified metastatic breast cancer (MBC) were reported. 14 patients with activating HER2 mutations were enrolled, 5/14 (36%, 90% CI: 15-61%) achieved clinical benefit, including one complete response, one partial response, and three stable disease for at least 6 months. The trial met its primary endpoint. The data provided proof of concept regarding HER2 mutation as a therapeutic target in non-amplified breast cancer. Accrual is ongoing for neratinib plus fulvestrant in ER+, HER2 mutated, non-amplified MBC. (ClinicalTrials.gov: NCT01670877)
LBA503: Trastuzumab Biosimilar MYL-14010 demonstrated equivalency to trastuzumab for treating HER2+ MBC
Heritage study is a phase III double blind study that compared MYL-14010 versus trastuzumab when combined with taxanes as first line treatment for HER2 positive MBC and demonstrated equivalency in efficacy, side effect profile, immunogenicity and population pharmacokinetics of the two agents. MYL-1401O has the potential to provide an affordable trastuzumab biosimilar for patients with HER2 positive breast cancer.
Abstract 504: Pertuzumab in HER2 positive breast cancer progressed on prior trastuzumab regimen
PHEREXA trial is a phase III study evaluating the benefit of adding pertuzumab to trastuzumab plus capecitabine in HER2+ MBC progressed on previous trastuzumab regimens. The median PFS was 9.0 months in the trastuzumab/capecitabine arm vs 11.1 months in the trastuzumab/capecitabine/pertuzumab arm, HR (95% CI) 0.82 (0.65-1.02), p=0.07, without statistically significant difference between the two arms. At this time, there is insufficient data to recommend pertuzumab in later lines of treatment.
Abstract 1011: Glutaminase as a novel therapeutic target for TNBC
Cancer cells have altered glucose metabolism and dependency on glutamine cell growth and survival. TNBC has increased expression of glutaminase which converts glutamine to glutamate and sensitivity to glutaminase inhibition in preclinical studies. A phase I study of CB-839, an oral small molecule inhibitor of glutaminase in combination with paclitaxel in TNBC was presented and demonstrated promising activity. Partial response was observed in three of 15 patients (20%), two of whom were heavily pretreated and with prior disease progression on paclitaxel in the metastatic setting. Additional clinical development is warranted.
Abstract 1000: Anthracycline remains an important component of adjuvant regimens for HER2- breast cancer
The ABC adjuvant trials (B-49, B-46-I/USOR 07132) were conducted to determine if TC (docetaxel and cyclophosphamide) for 6 cycles is non-inferior to combination regimens of doxorubicin/cyclophosphamide with docetaxel or paclitaxel (TaxAC) in women with resected high-risk, HER2-negative breast cancer. The primary endpoint of the study was invasive disease free survival (iDFS). With 399 iDFS events, 4 year iDFS is 88.2 percent for TC versus 90.7 percent for TaxAC. HR=1.23, 95 percent CI (1.01-1.5), p=0.04. TC was inferior to TaxAC. Longer follow-up should clarify the clinical utility of these initial findings.