Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study.

PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

Anti-CD20-atezolizumab-polatuzumab vedotin in relapsed/refractory follicular and diffuse large B-cell lymphoma.

PURPOSE: New therapies are needed for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase 1b, open-label trial evaluated two anti-CD20-based triplet combinations. METHODS: Patients with R/R follicular lymphoma (FL; n = 13) were treated with obinutuzumab, atezolizumab, and polatuzumab vedotin (G-atezo-pola; 1.4 mg/kg/1.8 mg/kg) and patients with R/R diffuse large B-cell lymphoma (DLBCL; n = 23) received rituximab (R)-atezo-pola. The primary efficacy endpoint was complete response (CR) at end of induction (EOI) by PET-CT (investigator assessed; modified Lugano 2014 criteria). Safety endpoints were also assessed. RESULTS: 13 FL patients were treated and evaluable for safety; 2/23 DLBCL patients did not receive treatment and were not included in the safety population. Median observation time was 23.3 and 5.7 months in the FL and DLBCL cohorts, respectively. At EOI, CR rates in FL patients treated with G-atezo-pola at pola doses of 1.4 mg/kg (N = 3) and 1.8 mg/kg (N = 7) were 33% and 14%, respectively. In DLBCL patients receiving R-atezo-pola, the CR rate at EOI was 13%. In the FL cohort, 62% of patients experienced a grade 3-5 adverse event (AE; including two deaths) and 31% developed a serious AE (SAE). In DLBCL patients, R-atezo-pola was associated with a lower incidence of grade 3-5 AEs (24%; one death) and SAEs (10%). In both cohorts, the most common grade 3-5 AEs were hematologic toxicities. CONCLUSION: Based on these safety issues, considered as related specifically to G-atezo-pola, and limited efficacy, no further development of either combination is planned. TRIAL REGISTRATION: NCT02729896; Date of registration: April 6, 2016.

Safety and efficacy of atezolizumab with rituximab and CHOP in previously untreated diffuse large B-cell lymphoma.

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) and is curative in ∼60% of patients. Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets programmed death-ligand 1 and has previously shown antitumor activity in several tumor types. In a phase 1b/2 trial (NCT02596971), we evaluated the safety and efficacy of atezolizumab in combination with R-CHOP (atezo-R-CHOP; for 6-8 cycles) in patients with previously untreated DLBCL. Patients achieving a complete response (CR) at the end of induction received consolidation therapy with atezolizumab on day 1 of each 21-day cycle for an additional 17 cycles. Overall, 42 patients with DLBCL were included in this analysis. The primary endpoint, CR rate at the end of induction, as assessed by an independent review committee (modified Lugano 2014 criteria), was 77.5% (95% confidence interval [CI], 64.0-87.7; n = 40). Investigator-assessed progression-free survival and overall survival at 3 years were 77.4% (95% CI, 59.7-88.0) and 87.2% (95% CI, 71.9-94.5), respectively. All treated patients experienced ≥1 adverse event (AE; 32 patients [76.2%] had grade 3-4 AE). One patient had a fatal AE (unconfirmed progressive multifocal leukoencephalopathy) that was considered related to atezolizumab and rituximab, and 17 patients (40.5%) experienced atezolizumab-related AEs of special interest. In previously untreated patients with DLBCL, atezo-R-CHOP demonstrated encouraging clinical efficacy and a safety profile consistent with the known toxicities of the individual drugs. This trial was registered at www.clinicaltrials.gov as #NCT02596971.

Safety and efficacy of atezolizumab with obinutuzumab and bendamustine in previously untreated follicular lymphoma.

Obinutuzumab (G) chemoimmunotherapy demonstrated improved progression-free survival (PFS) vs rituximab-based chemoimmunotherapy in patients with previously untreated follicular lymphoma (FL) in the GALLIUM trial. Atezolizumab (atezo) is a programmed death-ligand 1 inhibitor with a complementary mechanism of action to G by restoring cytotoxic T-cell function. We evaluated the safety and efficacy of atezo-G-bendamustine in patients with previously untreated FL in a phase Ib/II trial (#NCT02596971). A safety run-in phase was followed by an expansion phase with atezo-G-bendamustine induction and atezo-G maintenance for ≤24 months. Forty patients with previously untreated FL were enrolled and treated with atezo-G-bendamustine. The primary endpoint, complete response (CR) rate, assessed by an independent review committee (IRC; modified Lugano 2014 criteria) was 75.0% (95% confidence interval [CI], 61.3% to 85.8%). Three-year investigator-assessed PFS and overall survival rates were 80.9% (95% CI, 63.9% to 90.5%) and 89.3% (95% CI, 73.9% to 95.9%), respectively. At baseline, 21/40 patients had circulating lymphoma-specific clonotypes and underwent repeat testing at end of induction; all were minimal residual disease negative (10-5 sensitivity), with 16 (76.2%) CRs, 3 (14.3%) partial responses, and 2 (9.5%) with stable disease (IRC assessed). Grade 5 (fatal) adverse events (AEs) were reported in 5 patients. The efficacy of atezo-G-bendamustine in previously untreated FL did not appear superior to G-bendamustine efficacy as seen in the GALLIUM trial, and the addition of atezo to G-bendamustine was associated with an increased risk of AEs. Particularly due to the unfavorable safety profile, this regimen cannot be recommended in patients with previously untreated FL. This trial was registered at www.clinicaltrials.gov as #NCT02596971.

Combination of Atezolizumab and Tazemetostat in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Results From a Phase Ib Study.

BACKGROUND: The combination of atezolizumab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, and tazemetostat, an EZH2 inhibitor, may lead to selective epigenetic reprogramming, alter the tumor microenvironment, and provide additive or synergistic response to patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: This was an open-label, phase Ib study assessing the safety, tolerability, and preliminary efficacy of atezolizumab plustazemetostat in patients with R/R DLBCL. Atezolizumab (1200 mg) was administered via intravenous (IV) infusion on day 1 of each cycle and tazemetostat (800 mg) was given orally twice daily (BID) on days 1 to 21. Primary endpoints were safety and tolerability, and to identify a recommended phase II dose (RP2D) for atezolizumab. Secondary efficacy endpoints included response rate and duration of response. RESULTS: A total of 43 patients were enrolled, receiving a median of 3 prior lines of treatment (range: 1-9). The RP2D for atezolizumab was 1200 mg IV infusion every 3 weeks in combination with tazemetostat 800 mg BID. At the RP2D, adverse events reported in ≥20% patients were anemia(11 patients [26%]), fatigue (10 patients [23%]), and nausea (10 patients [23%]). Overall response rate was 16% (complete response rate: 7%). Median progression-free survival was 2 months (range: 0-24) and median overall survival was 13 months (range: 1-29). CONCLUSIONS: The combination of atezolizumab and tazemetostat was determined to be safe and tolerable. However, anti-tumor activity of the combination was modest.

Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study.

BACKGROUND: This was an open-label, phase 1b study assessing the safety, tolerability, preliminary efficacy and pharmacokinetics of the combination of atezolizumab and obinutuzumab in patients with relapsed/refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). There is a mechanistic rationale suggesting that this combination may enhance recruitment of both innate and adaptive immunity and be effective against CD20+ B-cell malignancies. MATERIALS AND METHODS: The study consisted of a safety evaluation stage and an expansion stage. Patients received obinutuzumab 1000 mg intravenously (IV) in cycle (C) 1, obinutuzumab plus atezolizumab 1200 mg IV for C2-8, and atezolizumab only from C9. Primary endpoints were to identify a recommended phase 2 dose (RP2D) for atezolizumab, and safety and tolerability in the safety and expansion stages. RESULTS: A total of 49 patients were enrolled (FL, n = 26; DLBCL, n = 23), with a median of 2 prior lines of treatment. The RP2D for atezolizumab was 1200 mg IV every 3 weeks. Adverse events reported in ≥ 20% of patients were fatigue (15 patients [31%]), nausea (13 patients [27%]), cough, and diarrhea (10 patients [20%] each). Objective response rate was 54% in the FL cohort (complete response [CR] rate: 23%) and 17% in the DLBCL cohort (CR: 4%). Median progression-free survival was 9 months for FL and 3 months for DLBCL. Median overall survival was not estimable for FL and 9 months for DLBCL. CONCLUSION: The combination of obinutuzumab and atezolizumab was determined to be safe and tolerable, with no new toxicities observed.

Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study.

BACKGROUND: A subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase in one ready-to-use, fixed-dose combination vial (pertuzumab, trastuzumab, and hyaluronidase-zzxf) was approved by the US Food and Drug Administration (FDA) on June 29, 2020. We report the primary analysis of the FeDeriCa study, which was designed to assess the pharmacokinetics, efficacy, and safety of the fixed-dose subcutaneous formulation compared to intravenous pertuzumab plus trastuzumab in patients with HER2-positive early breast cancer in the neoadjuvant-adjuvant setting. METHODS: FeDeriCa, a randomised, open-label, international, multicentre, non-inferiority, phase 3 study, was done across 106 sites in 19 countries. Patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1, HER2-positive, operable, locally advanced, or inflammatory stage II-IIIC breast cancer, and a left ventricular ejection fraction of 55% or more were randomly assigned (1:1), using a voice-based or web-based response system, to receive intravenous pertuzumab (840 mg loading dose, followed by 420 mg maintenance doses) plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance doses) or the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (1200 mg pertuzumab plus 600 mg trastuzumab loading dose in 15 mL, followed by 600 mg pertuzumab plus 600 mg trastuzumab maintenance doses in 10 mL), both administered every 3 weeks with neoadjuvant chemotherapy. Patients were stratified by hormone receptor status, clinical stage, and chemotherapy regimen. The investigator selected one of the two protocol-approved standard chemotherapy regimens before randomisation. Four cycles of HER2-targeted therapy were administered concurrently with the taxane. After surgery, patients continued the HER2-targeted therapy to receive an additional 14 cycles (total of 18). The primary endpoint was non-inferiority of the cycle 7 pertuzumab serum trough concentration (Ctrough; ie, cycle 8 predose pertuzumab concentration) within the fixed-dose combination for subcutaneous injection versus intravenous pertuzumab plus trastuzumab in the per-protocol pharmacokinetic population (all enrolled patients who adhered to prespecified criteria for pharmacokinetic assessment). Non-inferiority was concluded if the lower bound of the 90% CI of the geometric mean ratio was 0·8 or higher. The safety population included all patients who received at least one dose of study medication, including chemotherapy or HER2-targeted therapy. Enrolment, neoadjuvant therapy, and surgery have been completed; adjuvant treatment and follow-up are ongoing. The trial is registered with ClinicalTrials.gov, NCT03493854. FINDINGS: Between June 14, 2018, and Dec 24, 2018, 252 patients were randomly assigned to the intravenous infusion group and 248 to the fixed-dose combination group. The geometric mean ratio of pertuzumab serum Ctrough subcutaneous to serum Ctrough intravenous was 1·22 (90% CI 1·14-1·31). The most common grade 3-4 adverse events occurring during neoadjuvant treatment with HER2-targeted therapy plus chemotherapy in 5% or more of patients were neutropenia (34 [13%] of 252 patients in the intravenous infusion group vs 35 [14%] of 248 patients in the fixed-dose combination group), decreased neutrophil count (31 [12%] vs 27 [11%]), febrile neutropenia (14 [6%] vs 16 [6%]), diarrhoea (12 [5%] vs 17 [7%]), and decreased white blood cell count (18 [7%] vs nine [4%]). At least one treatment-related serious adverse event was reported in 25 (10%) patients in the intravenous infusion group and 26 (10%) patients in the fixed-dose combination group. One patient in each treatment group had an adverse event that led to death (urosepsis in the intravenous infusion group and acute myocardial infarction in the fixed-dose combination group); neither death was related to HER2-targeted therapy. INTERPRETATION: The study met its primary endpoint: the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection provides non-inferior cycle 7 pertuzumab serum Ctrough concentrations to intravenous pertuzumab plus trastuzumab in the neoadjuvant setting with comparable total pathological complete response rates, supporting the FDA approval. Safety was similar between treatment groups, and in line with other pertuzumab, trastuzumab, and chemotherapy trials. Follow-up is ongoing for long-term outcomes, including efficacy and long-term safety. FUNDING: F Hoffmann-La Roche and Genentech.