IMpassion031: Results from a phase III study of neoadjuvant atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC)

At ESMO 2020, Dr Nadia Harbeck presented the primary analysis for IMpassion 031, a phase III trial evaluating the efficacy and safety of atezolizumab versus placebo in combination with neoadjuvant chemotherapy consisting of sequential nab-paclitaxel and doxorubicin-cyclophosphamide for treatment of early-stage TNBC.

Figure 1. Overview of IMpassion 031 study design, inclusion criteria, endpoints and stratification factors

Atezolizumab plus chemotherapy resulted in a statistically significant and clinically meaningful 16.5% increase in pCR rate versus placebo plus chemotherapy (57.6% vs 41.1%) in the ITT population (p = 0.0044). The benefit was observed regardless of PD-L1 status and across clinical subgroups. The median EFS was not reached in either arm (HR, 0.76; 95% CI: 0.40, 1.44), and while the trend supports the pCR benefit seen with atezolizumab plus chemotherapy, the data is not matured to make conclusions on the EFS benefit

Figure 2. Co-primary endpoint pathologic complete response in ITT and PD-L1 positive tumours

The safety profile of atezolizumab plus chemotherapy was consistent with the known risks of the individual study drugs. Grade 3-4 AEs and discontinuation rates were well balanced while rates of treatment-related serious AEs were higher in the atezolizumab plus chemotherapy arm (22.6% vs 15.6%).

Table 1. Adverse events of special interest (AESI) in the neoadjuvant phase

In conclusion, the combination of atezolizumab with neoadjuvant chemotherapy for stage II-III TNBC provides clinically meaningful pCR benefit with an acceptable safety profile independent of PD-L1 status.

IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab plus nab-paclitaxel vs placebo plus nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer

Dr Leisha Emens shared the final OS analysis from IMpassion 130, a phase III trial evaluating atezolizumab plus nab-paclitaxel (A +nP) vs placebo plus nab-paclitaxel (P + nP) in previously untreated locally advanced or metastatic triple-negative breast cancer. The primary PFS analysis demonstrated statistically significant benefit with A + nP vs P + nP in the ITT and PD-L1 IC+ populations. While OS analyses were not formally tested due to the statistical analysis plan, a clinically meaningful improvement was observed in the PD-L1 IC+ population with a 9.5 month OS improvement (HR 0.62, 95% CI: 0.45, 0.86) in the first interim analysis and a 7 month OS improvement (HR 0.71,95% CI: 0.54, 0.93) in the second interim analysis.

In this final and mature OS analysis, a consistent clinically meaningful OS was observed in the PD-L1 IC+ population with 7.5 month mOS improvement with A + nP vs P + nP (HR 0.67, 95% CI: 0.53-0.86). With the longer follow up, A + nP remained safe and tolerable with no new safety signals identified. Importantly, landmark analysis of 3-year survival rates was higher with A + nP vs P + nP in the PD-L1 population (36% vs. 22%).

Based on findings from this study, international guidelines recommend atezolizumab in combination with nab-paclitaxel as a treatment option for previously untreated mTNBC whose tumours express PD-L1 on immune cells.

Figure 3. Overall Survival in the PD-L1 IC+ Population

IMpassion131: Primary results from a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel ± atezolizumab (Pac + A) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC)

In contrast to the IMpassion 130 study results, the primary analysis for IMpassion 131 presented by Dr David Miles showed that the additional of atezolizumab to paclitaxel did not significantly improve PFS or OS in the PD-L1 IC+ and ITT populations.

Figure 4. Progression Free Survival in the PD-L1 IC+ Population

Grade 3-4 AEs rates were well balanced between arms (43% vs 49% in Pac + A) and the safety profile of the Pac + A was consistent with the known effects of the individual study drugs. Findings from this study underlines the need to further explore the contrasting benefits seen in IMpassion 130.

ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC)

Dr Aditya Bardia presented the primary results from ASCENT, a phase III study evaluating SG (10 mg/kg IV) against single-agent TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) in mTNBC patients with relapsed/refractory metastatic disease after ≥2 prior chemotherapies, including prior taxane use. This PFS analysis was based on central assessment in the brain metastases-negative population.

The primary endpoint of median PFS was found to be significantly longer with SG versus TPC (5.6 vs 1.7 months; HR, 0.41; P<0.0001) and consistent across subgroups. There was also a significant improvement in mOS with SG (12.1 vs 6.7 months; HR, 0.48; P<0.0001) with a higher ORR of 35% for SG versus 5% for TPC (P<0.0001).

In the safety population comprising of patients who received ≥1 dose of study drug, key treatment-related grade ≥3 adverse events with SG vs TPC were neutropenia (51% vs 33%), diarrhea (10% vs <1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%). There were no grade >3 neuropathy or interstitial lung disease, and no treatment-related deaths were reported with SG.

In conclusion, findings of the ASCENT study highlight the clinical utility of the antibody–drug conjugate SG in patients with pretreated mTNBC.

Patient (pt) preference for the pertuzumab-trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) in HER2-positive early breast cancer (EBC): Primary analysis of the open-label, randomised crossover PHranceSCa study

Dr Joyce O’Shaughnessy presented the primary analysis of PHranceSCa, an open-label, randomised cross-over study evaluating patient preference and satisfaction with subcutaneous versus intravenous (IV) treatment with pertuzumab (P) plus trastuzumab (H).

Figure 5. Overview of PHranceSCa study design, inclusion criteria, objectives and stratification factors

At the primary analysis, 85% of patients (136/160; 95% CI: 79–90%) preferred PH FDC SC; 14% (22/160) preferred P + H IV. The main reasons for preferring PH FDC SC were “less time in clinic” (42%) and “more comfortable during administration” (26%). 87% of patients chose to continue treatment with PH FDC SC versus 13% for P + H IV. More patients indicated that they were “very satisfied” or “satisfied” with PH FDC SC versus P + H IV (90% vs 83%). Healthcare Professionals (HCPs) indicated that PH FDC SC provided marked time savings and required fewer resources in comparison to P + H IV (Table 2).

Table 2. HCP Perception of PH FDC SC versus P +H IV

With regards to the safety results, the findings from PHranceSCa support those seen with PH FDC SC in the FeDeriCa study, with no new safety signals, including when switching from IV to SC and vice-versa. PH FDC SC was generally well tolerated, with a safety profile in line with previous studies using P + H IV. There was a low incidence of SAE and grade ≥3 AEs with PH FDC with no grade 4 or 5 AEs reported during the study at the clinical cut-off date (Table 3). There were more injection site reactions with PH FDC SC, all of which were grade 1 and 2 and none led to discontinuations of the treatment.

Table 3. Overview of Adverse Events from PHranceSCa Study

PH FDC SC has been approved by the U.S. Food and Drug Administration based on data from FeDeriCa and PHranceSCa to treat adult patients with HER2-positive breast cancer that has spread to other parts of the body, and for treatment of adult patients with early HER2-positive breast cancer.

PALLAS: A randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy (ET) alone for HR+/HER2- early breast cancer

Dr Erica Mayer presented findings from the phase III trial PALLAS, comparing 2 years palbociclib with adjuvant ET versus ET alone in patients with stage II-III HR+/HER2- breast cancer who were within 12 months of diagnosis and 6 months of initiating adjuvant ET.

After a median follow-up of 23.7 months, the primary endpoint, iDFS, was similar between the two arms, with 3-year iDFS of 88.2% for palbociclib and ET versus 88.5% for ET alone (HR 0.93, 95% CI 0.76-1.15, p = 0.51). Similarly, there was no significant difference in DRFS between the two arms (HR 1.00, 95% CI 0.79-1.27, p = 0.997). No subgroups appeared to receive benefit from the addition of palbociclib to standard adjuvant ET. At the 2^nd interim analysis, futility boundary for iDFS was crossed with IDMC recommending discontinuation of palbociclib in the remaining patients.

With regard to adverse events, 99.4% of patients on palbociclib + ET experience treatment emergent adverse events versus 88.6% on ET alone. Grade 3/4 neutropenia was more common with palbociclib (61.3% vs 0.4%) but febrile neutropenia was uncommon (1.0%). Other all-grade toxicities including leukopenia, fatigue, thrombocytopenia, anemia, upper respiratory tract infection, and alopecia were more common with palbociclib + ET. Notably, the rate of premature discontinuation of palbociclib was 42.2% at time of data cut-off.

In conclusion, the addition of palbociclib to adjuvant ET did not prolong IDFS versus ET alone in patients with stage II-III HR+/HER2- breast cancer.

monarchE: Abemaciclib in high risk early breast cancer (eBC)

Dr Steven Johnston presented the findings from the phase III study, monarchE, evaluating abemaciclib (150 mg BID for 2 years) plus ET versus ET alone in HR+/HER2-, high risk eBC patients who have completed primary treatment. The study included patients with ≥4 positive nodes, or 1-3 nodes and at least one of the following: tumor size ≥5 cm, histologic grade 3, or central Ki-67 ≥20%. This was a pre-planned efficacy interim analysis triggered following approximately 75% of total required IDFS events.

At a median follow up of 15.5 months, the addition of Abemaciclib to ET resulted in higher IDFS rates of 92.2% versus 88.7% with ET alone. This difference was shown to be statistically significant with a corresponding 25.3% reduction in the risk of an IDFS event (HR: 0.747, 95% CI: 0.598, 0.932, p=.0096). A similar improvement was observed for DRFS with 2-year DRFS rates of 93.6% with abemaciclib plus ET and 90.3% with ET alone (HR: 0.717, 95% CI: 0.559, 0.920). There was a consistent benefit across all pre-specified subgroups for both IDFS and DRFS.

Treatment-emergent AEs were consistent with the known safety profile of abemaciclib. The most frequent AEs were diarrhea (82.2% vs 7.1%), neutropenia (44.6% vs 5.0%) and fatigue (38.4% vs 15.5%) in the abemaciclib arm and arthralgia (31.3% vs 20.5%) and hot flush (21.0% vs 14.1%) in the control arm. Diarrhea occurred early (median time to onset for any grade of 8 days), was short-lived (median duration for grades 2 and 3 of 5 to 6 days), and was managed with antidiarrheal medication and dose adjustments as per the protocol. 16.6% of patients discontinued abemaciclib due to AEs whilst 0.8% discontinued endocrine therapy due to AEs.

In conclusion, monrachE demonstrated that abemaciclib in combination with standard adjuvant ET significant improves IDFS in HR+/HER2- high risk eBC patients.

monarchE: Abemaciclib in high risk early breast cancer (eBC)

Dr Erika Hamilton presented the final analysis of nextMonarch, a phase II trial of abemaciclib in women with heavily pretreated HR+/HER2 mBC whose disease progressed on or after ET and chemotherapy. Patients were randomized 1:1:1 to abemaciclib 150mg + tamoxifen 20 mg (A+T), or abemaciclib 150 mg (A-150) or abemaciclib 200 mg plus prophylactic loperamide (A-200). Data presented represents the final overall analysis which was planned 24 months after last patient entered treatment. This study was not powered to test OS superiority.

The mOS in the A+T vs A-200 cohort of patients was 24.2 months vs 17.0 months (HR 0.620, 95% CI: 0.397, 0.969, p=0.034). The mOS in the A-150 cohort of patients was 20.8 months which was found to be comparable to the A-200 arm (HR 0.956, 95% CI: 0.635, 1.438, p=0.832). There was no significant difference in the primary PFS endpoint and ORR between the arms at the 24-month analysis, which was consistent with the primary analysis.

Incidence of adverse events (AEs) were similar across the arms with no new safety signals observed. Common treatment-emergent AEs across all abemaciclib arms that occurred in ≥25% of patients include diarrhea (61.1%), neutropenia (49.6%), anemia (40.6%), nausea (36.3%), leukopenia (30.8%), fatigue (29.9%) and abdominal pain (27.4%).

In conclusion, the addition tamoxifen to abemaciclib showed improved mOS compared to abemaciclib monotherapy in heavily pretreated HR+/HER2- mBC patients.

Editor: Tira Tan Jing Ying

References:

Harbeck N, et al. IMpassion031: Results from a phase III study of neoadjuvant atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC). Annals of Oncology (2020) 31 (S4): S1144. doi.org/10.1016/j.annonc.2020.08.2239.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V6.2020. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Published 8 September 2020. Accessed 26 October 2020.

Emens, LA, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. Annals of Oncology (2020) 31 (S4): S1148. doi.org/10.1016/j.annonc.2020.08.2244.

Miles, DW, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). Annals of Oncology (2020) 31 (S4): S1147-S1148. doi.org/10.1016/j.annonc.2020.08.2243.

Bardia A, et al. ASCENT: A randomized phase 3 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Annals of Oncology (2020) 31 (S4): S1149-S1150. doi.org/10.1016/j.annonc.2020.08.2245.

O’Shaughnessy J, et al. 165MO Patient (pt) preference for the pertuzumab-trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) in HER2-positive early breast cancer (EBC): Primary analysis of the open-label, randomised crossover PHranceSCa study. Annals of Oncology (2020) 31 (S4): S306-S307. doi.org/10.1016/j.annonc.2020.08.287.

Hamilton EP, et al. 273O nextMONARCH: Final overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with HR+, HER2- metastatic breast cancer. Annals of Oncology (2020) 31 (S4): S348. doi.org/10.1016/j.annonc.2020.08.375.

Johnston SRD, et al. Abemaciclib in high risk early breast cancer. Annals of Oncology (2020) 31 (S4): S1143-S1144. doi.org/10.1016/j.annonc.2020.08.2238.

Mayer EK, et al. LBA12 PALLAS: A randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone for HR+/HER2- early breast cancer. Annals of Oncology (2020) 31 (S4): S1145. doi.org/10.1016/j.annonc.2020.08.2240.