This phase 1b multicohort study assessed 33 patients with advanced triple-negative breast cancer treated with atezolizumab plus nab-paclitaxel to examine its safety, tolerability, and preliminary clinical activity.
Key Points
Question
Is atezolizumab plus nab-paclitaxel safe and clinically active in patients with advanced triple-negative breast cancer?
Findings
This phase 1b multicohort study assessed atezolizumab plus nab-paclitaxel in 33 patients with advanced triple-negative breast cancer and revealed a manageable safety profile with an objective response rate of 39.4% and durable antitumor responses observed in several patients. Serial biopsy analysis did not reveal an association between biomarker changes and clinical activity, and the addition of nab-paclitaxel did not abrogate atezolizumab-mediated T-cell activation in the periphery.
Meaning
The atezolizumab and nab-paclitaxel combination was safe and clinically active in this phase 1b study.
Abstract
Importance
The humanized monoclonal antibody atezolizumab targets programmed death-ligand 1 and has demonstrated durable single-agent activity in a subset of metastatic triple-negative breast cancers. To extend the observed activity, combinatorial approaches are being tested with standard cytotoxic chemotherapies known to induce immunogenic tumor cell death.
Objective
To examine the safety, tolerability, and preliminary clinical activity of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancers.
Design, Setting, and Participants
This phase 1b multicohort study enrolled 33 women with stage IV or locally recurrent triple-negative breast cancers and 0 to 2 lines of prior chemotherapy in the metastatic setting from December 8, 2014, to April 30, 2017, at 11 sites in the United States. The median follow-up was 24.4 months (95% CI, 22.1-28.8 months).
Interventions
Patients received concurrent intravenous atezolizumab and intravenous nab-paclitaxel (minimum 4 cycles).
Main Outcomes and Measures
The primary end point was safety and tolerability. Secondary end points included best overall response rate by Response Evaluation Criteria in Solid Tumors, version 1.1; objective response rate; duration of response; disease control rate; progression-free survival; overall survival; and biomarker analyses.
Results
The 33 women had a median age of 55 years (range, 32-84 years) and received 1 or more doses of atezolizumab. All patients (100%) experienced at least 1 treatment-related adverse event, 24 patients (73%) experienced grade 3/4 adverse events, and 7 patients (21%) had grade 3/4 adverse events of special interest. No deaths were related to study treatment. The objective response rate was 39.4% (95% CI, 22.9%-57.9%), and the median duration of response was 9.1 months (95% CI, 2.0-20.9 months). The disease control rate was 51.5% (95% CI, 33.5%-69.2%). Median progression-free survival and overall survival were 5.5 months (95% CI, 5.1-7.7 months) and 14.7 months (95% CI, 10.1-not estimable), respectively. Concurrent nab-paclitaxel neither significantly changed biomarkers of the tumor immune microenvironment (programmed death-ligand 1, tumor-infiltrating lymphocytes, CD8) nor impaired atezolizumab systemic immune activation (expansion of proliferating CD8+ T cells, increase of CXCL10 chemokine).
Conclusions and Relevance
In this phase 1b trial for metastatic triple-negative breast cancers, the combination of atezolizumab plus nab-paclitaxel had a manageable safety profile. Antitumor responses were observed, including in patients previously treated with a taxane.
Trial Registration
ClinicalTrials.gov identifier: NCT01633970
Introduction
Triple-negative breast cancer (TNBC) has a poor prognosis compared with other subtypes, particularly when metastatic.1,2,3 Standard chemotherapy for metastatic TNBC (mTNBC) has suboptimal efficacy and considerable toxicity.4 Evidence suggests that subsets of TNBC are immunogenic based on the presence of tumor-infiltrating lymphocytes (TILs) in early-stage tumors.5,6,7,8,9 Higher percentages of TILs were associated with response to atezolizumab10 and pembrolizumab, particularly in patients with previously untreated mTNBC.11 Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) has been associated with increased activity of atezolizumab in lung,12 bladder,13 and renal cancers.14 Studies of TNBC have demonstrated increased PD-L1 expression and TILs vs non-TNBC.15,16,17,18 Together, this forms a rationale for the study of PD-L1/programmed death-1 (PD-1) immunotherapies in TNBC.
Atezolizumab, an engineered, humanized immunoglobulin G1 monoclonal antibody, targets PD-L1 in the tumor microenvironment and reactivates T cells by inhibiting binding of PD-L1 to PD-1 and B7.1.19,20,21 Atezolizumab is approved for urothelial and lung cancer indications.22,23
Anti–PD-L1/PD-1 agents are clinically active in mTNBC, but low response rates to single-agent treatment have generated interest in combination therapy.10,24,25,26,27 Combination with chemotherapy may be synergistic by targeting different steps in the cancer immunity cycle.28 Chemotherapy can result in tumor antigen release that may elicit antitumor immunity,28,29 enhance the antigenicity of cancer cells by increasing major histocompatibility complex expression, increase PD-L1 expression on tumor cells,30 and increase CD8+ TILs.31 By enhancing T-cell responses, atezolizumab may result in improved response rates and durability vs chemotherapy alone.28 Synergism has been demonstrated in preclinical models.32
Nab-paclitaxel is a nanoparticle albumin–bound form of paclitaxel that is approved for treatment of metastatic breast cancer. Because it does not require steroid premedication, which has potential immunosuppressive effects33 and has shown efficacy as a first-line combination partner with biologic therapies,34 nab-paclitaxel is a rational partner for testing chemoimmunotherapy combinations.
This arm of the present phase 1b study aimed to examine the safety, tolerability, and preliminary clinical activity of atezolizumab plus nab-paclitaxel in the treatment of mTNBC (GP28328; NCT01633970). Prior to the initiation of this arm of the study, GP28328 demonstrated the safety and tolerability of combining atezolizumab with 3 standard doublet chemotherapies, including 2 taxane-based regimens (carboplatin plus paclitaxel and carboplatin plus nab-paclitaxel), in patients with non–small cell lung cancer.35 Based on this, the evaluation of the atezolizumab plus nab-paclitaxel combination in the present study did not include a dose-ranging phase. The majority of patients were enrolled in a serial biopsy cohort to interrogate the immunodynamic effects of nab-paclitaxel and the combination with atezolizumab on the tumor microenvironment and predictive biomarker analyses.
Methods
Study Design and Participants
The GP28328 study is a multicenter, multicohort phase 1b study of atezolizumab plus chemotherapy in the treatment of advanced solid tumors (Supplement 1). We report the mTNBC cohort. Patients had histologically confirmed stage IV or locally advanced unresectable TNBC (per institutional standards). Other key inclusion criteria included Eastern Cooperative Oncology Group performance status 0 or 1 and availability of archival and/or freshly collected tumor specimens. Patient race and ethnicity were self-reported demographics.
Patients were excluded if they had more than 2 prior systemic cytotoxic regimens for metastatic or locally advanced TNBC, had received a taxane within 6 months prior to enrollment, or had untreated or active central nervous system metastases. This study was conducted in accordance with US Food and Drug Administration regulations, the International Conference on Harmonisation E6 Guideline for Good Clinical Practice, and applicable local, state, and federal laws, as well as other applicable country laws. The study was approved by the institutional review boards at participating institutions. The specific sites included Beth Israel Deaconess Medical Center, Carolina BioOncology Institute, Dana-Farber Cancer Institute, Duke University Medical Center, Georgetown Lombardi Comprehensive Cancer Center at Georgetown University, New York University Perlmutter Cancer Center, Massachusetts General Hospital, Sarah Cannon Research Institute, University of Colorado Cancer Center, and Yale University. All patients gave written informed consent and agreed to provide archival and/or freshly collected tumor tissue.
Procedures
In the safety cohort, atezolizumab and nab-paclitaxel were administered concurrently (eFigure 1 in Supplement 2). Patients received intravenous atezolizumab, 800 mg, on days 1 and 15 of each cycle every 2 weeks and intravenous nab-paclitaxel, 125 mg/m2, on days 1, 8, and 15 of each cycle (3 weeks on, 1 week off).
In the serial biopsy cohort, patients received nab-paclitaxel alone on days 1 and 8 of cycle 1, followed by concurrent nab-paclitaxel and atezolizumab, 800 mg, starting on day 15. Subsequent cycles were administered per the safety cohort. Tumor biopsies for correlates were collected predose (≥7 days before cycle 1, day 1), post–nab-paclitaxel dose (cycle 1, between days 10 and 15 prior to administration of the first dose of atezolizumab), and post–atezolizumab plus nab-paclitaxel (approximately 4 weeks after first atezolizumab dose), based on known early effects of chemotherapeutics on biomarkers of the tumor microenvironment and expected delayed immune effects of the combination.36
Nab-paclitaxel was administered for a minimum of 4 cycles in the absence of disease progression or unacceptable toxic effects. Nab-paclitaxel could be discontinued independently of atezolizumab, and atezolizumab with or without nab-paclitaxel could be continued while patients experienced clinical benefit per investigator.
Study End Points
The primary objective of the mTNBC cohort of the GP28328 study was to evaluate the safety and tolerability of atezolizumab administered with nab-paclitaxel. Secondary objectives included pharmacokinetics (not reported herein) and preliminary assessment of the antitumor activity of the combination (best overall response, objective response rate [ORR], duration of objective response [DOR], disease control rate [DCR], progression-free survival [PFS], and overall survival [OS]). Exploratory objectives included a preliminary assessment of pharmacodynamic and predictive biomarkers.
Study Assessments
The incidence, nature, and severity of adverse events (AEs) and laboratory abnormalities were graded per the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.37 Tumor assessments occurred every 2 cycles for the first year and every 4 cycles thereafter or as clinically indicated. Patients who discontinued study treatment for reasons other than disease progression had tumor assessments every 12 weeks until death, disease progression, or initiation of new systemic anticancer therapy.
Biomarkers
The PD-L1 expression was centrally evaluated by immunohistochemical analysis in archival and fresh tumor specimens with the VENTANA PD-L1 (SP142) assay (Ventana Medical Systems, Inc), which is optimized to detect PD-L1 on both TCs and ICs.22 The PD-L1 expression on TCs was scored as cells expressing PD-L1 as a percentage of TCs (TC0: <1% TCs expressing PD-L1; TC1/2/3: ≥1% TCs expressing PD-L1), whereas PD-L1 expression on ICs was scored as ICs expressing PD-L1 as a percentage of tumor area (IC0: <1% ICs expressing PD-L1; IC1/2/3: ≥1% ICs expressing PD-L1).
The CD8+ T cells in tumors were assessed with immunohistochemical analysis (clone C8/144B; Dako). Stromal TILs were evaluated in hematoxylin-eosin–stained slides per TILs Working Group 2014 recommendations.38 HistoGeneX Laboratories performed the assessments.
Peripheral blood mononuclear cells were analyzed for CD3, CD8, HLA-DR, and Ki-67 expression by fluorescence-activated cell sorting analysis at the central LabCorp laboratory. Blood was collected predose on day 1 of cycles 1, 2, and 4.
Peripheral blood mononuclear cells RNA was isolated using the QIAGEN RNeasy extraction kit (Precision Inc). The CXCL10 RNA expression was analyzed by LabCorp using a customized NanoString CodeSet (NanoString Technologies, Inc).
Statistical Analysis
This study was not designed to make explicit power and type I error considerations but to obtain preliminary safety, clinical activity, and pharmacokinetic information in this patient population. Analyses were based on all patients who received any amount of study treatment (safety-evaluable population). The ORR and DCR with corresponding 95% CIs were calculated using the Clopper-Pearson method. The DOR, PFS, and OS were assessed by the Kaplan-Meier method, with 95% CIs for median PFS and OS estimated using the Brookmeyer-Crowley method.
Objective response was defined as confirmed complete response (CR) or partial response (PR) by RECIST. Disease control was defined as the proportion of patients with confirmed CR or PR, or stable disease maintained for 24 or more weeks. The PFS was time from the first study treatment to first occurrence of progression or death, whichever occurred first. The DOR was first occurrence of a documented objective response until progression or death from any cause. The OS was first dose of study treatment until death from any cause.
Statistical analysis of biomarker analyses used t tests for 2-group analyses or analysis of variance for multiple groups.
Results
Patient Characteristics
Thirty-three patients (8 in the safety cohort and 25 in the serial biopsy cohort) were enrolled and treated in the mTNBC cohort of the GP28328 study (Figure 1). Baseline characteristics are given in Table 1. Thirteen patients had received no prior systemic regimens for metastatic disease and were treated in the first-line (1L) setting, whereas 20 patients were treated in the second-line or later (2L+) setting. Most patients (88% [n = 29]) had previously received a taxane.
Figure 1. Study Flowchart.
The study flowchart shows enrolled and treated patients in the metastatic triple-negative breast cancer cohort of this phase 1b study. The number of patients screened for eligibility for this cohort of patients is not available. Treatment and study discontinuations and reasons are depicted. No patients were lost to follow-up. The safety and biomarker expansion cohorts are also shown with a breakdown of evaluable samples for each biomarker (programmed death-ligand 1 [PD-L1], CD8, and tumor-infiltrating lymphocytes [TILs]) and matched pretreatment and posttreatment samples available.
Table 1. Baseline Characteristics of 33 Patients.
| Characteristic | No. (%) |
|---|---|
| Age, median (range), y | 55 (32-84) |
| 18-40 | 7 (21) |
| 41-64 | 21 (64) |
| ≥65 | 5 (15) |
| Sex | |
| Male | 0 |
| Female | 33 (100) |
| Ethnicity | |
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 33 (100) |
| Race | |
| White | 25 (76) |
| Black or African American | 3 (9) |
| Asian | 2 (6) |
| Multiple | 1 (3) |
| Other | 2 (6) |
| Histology | |
| Ductal | 25 (76) |
| Ductal/lobular | 4 (12) |
| Ductal/medullary | 1 (3) |
| Ductal/tubular | 1 (3) |
| Ductal/other | 1 (3) |
| Tubular | 1 (3) |
| ECOG PS | |
| 0 | 6 (18) |
| 1 | 27 (82) |
| Site of metastases | |
| Visceral | 19 (58) |
| Liver | 11 (33) |
| Nodal only | 2 (6) |
| Other | 12 (36) |
| LDH, ULN | |
| <1.5 | 27 (82) |
| ≥1.5 | 6 (18) |
| ≥2.5 | 3 (9) |
| No. of prior systemic cancer therapies in the metastatic settinga | |
| 0 | 13 (39) |
| ≥1a | 20 (61) |
| Prior taxane use | 29 (88) |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; LDH, lactate dehydrogenase; ULN, upper limit of normal.
One patient had received 3 prior lines of treatment in the metastatic setting, which was not allowed per eligibility; this patient was included in all analyses.
Safety
All 33 patients received 1 or more doses of atezolizumab at time of data cutoff (April 30, 2017). The median duration of safety follow-up was 6.9 months (range, 1.7-30.3 months). Median duration of exposure was 5.6 months (range, 0-30 months) for atezolizumab and 4.7 months (range, 0-24 months) for nab-paclitaxel. A median of 13 doses (range, 1-64 doses) of atezolizumab and 14 doses (range, 2-80 doses) of nab-paclitaxel were administered.
All patients experienced 1 or more treatment-related AE (Table 2); the most frequent AEs were neutropenia (70% [n = 23]), fatigue (67% [n = 22]), alopecia (42% [n = 14]), diarrhea (39% [n = 13]), peripheral sensory neuropathy (36% [n = 12]), peripheral neuropathy (30% [n = 10]), and nausea (30% [n = 10]).
Table 2. Treatment-Related and Immune-Related Grade 3/4 Adverse Events (AEs) Occurring in ≥1 Patienta.
| Adverse Eventb | Grade 3/4 AEs (N = 33), No. (%) | All-Grade AEs (N = 33), No. (%) |
|---|---|---|
| Treatment-related AEs | ||
| All | 24 (73) | 33 (100) |
| Neutropenia and decreased neutrophil count | 15 (46) | 23 (70) |
| Thrombocytopenia and decreased platelet count | 3 (9) | 5 (15) |
| Diarrhea | 2 (6) | 13 (39) |
| Anemia | 2 (6) | 8 (24) |
| White blood cell count decreased | 2 (6) | 4 (12) |
| Pneumonia | 2 (6) | 2 (6) |
| Neuropathy peripheral | 1 (3) | 10 (30) |
| Myalgia | 1 (3) | 5 (15) |
| Bone pain | 1 (3) | 4 (12) |
| Aspartate aminotransferase increased | 1 (3) | 3 (9) |
| Pneumonitis | 1 (3) | 3 (9) |
| Colitis | 1 (3) | 1 (3) |
| Syncope | 1 (3) | 1 (3) |
| Febrile neutropenia | 1 (3) | 1 (3) |
| Type 1 diabetes mellitus | 1 (3) | 1 (3) |
| Paronychia | 1 (3) | 1 (3) |
| Pneumonia mycoplasma | 1 (3) | 1 (3) |
| AESIc | ||
| All | 7 (21) | 30 (91) |
| Aspartate aminotransferase increased | 3 (9) | 5 (15) |
| Alanine aminotransferase increased | 1 (3) | 3 (9) |
| Pneumonitis | 1 (3) | 3 (9) |
| Drug reaction with eosinophilia and systemic symptoms | 1 (3) | 1 (3) |
| Type 1 diabetes mellitus | 1 (3) | 1 (3) |
| Colitis | 1 (3) | 1 (3) |
Abbreviations: AESI, adverse event of special interest; MedDRA, Medical Dictionary for Regulatory Activities.
Including corresponding incidences of all-grade AEs. Additional treatment-related AEs of grades 1 or 2 (occurring in ≥10 patients) included fatigue (67% [n =22]), alopecia (42% [n = 14]), peripheral sensory neuropathy (36% [n = 12]), and nausea (30% [n =10]).
The AEs were encoded using MedDRA, version 20.0. All counts represent patients. Multiple occurrences of the same AE in 1 individual were counted once at the highest grade for this preferred term. Any AEs with onset from first dose of study drug through 30 days after last dose of study drug or initiation of another anticancer therapy (whichever occurred first) were included.
Adverse events of special interest are defined as both diagnosed immune conditions and signs and symptoms potentially representative of immune-related events.
Grade 3/4 events attributed, at least in part, to atezolizumab were observed in 24 patients (73% [n = 24]) (Table 2). The most frequent grade 3/4 events were neutropenia and decreased neutrophil count (46% [n = 15]), thrombocytopenia and decreased platelet count (9% [n = 3]), pneumonia (6% [n = 2]), anemia (6% [n = 2]), diarrhea (6% [n = 2]), and white blood cell count decreased (6% [n = 2]). Febrile neutropenia was observed in 1 patient (3%). The most common grade 3/4 AEs attributed exclusively to atezolizumab were diarrhea (6 % [n = 2]) and colitis (3% [n = 1]).
Most patients (91% [n = 30]) experienced 1 or more AEs of special interest (AESI) (Table 2); the most frequent were rash (39% [n = 13]), pruritus (27% [n = 9]), increased aspartate aminotransferase levels (15% [n = 5]), dry skin (12% [n = 4]), and pyrexia (12% [n = 4]). Grade 3/4 AESIs were seen in 21% (n = 7) of patients, and the most frequent was increased aspartate aminotransferase levels (9% [n = 3]).
Three patients (9%) discontinued atezolizumab for treatment-related toxic effects: 1 following prolonged asymptomatic grade 2 aspartate aminotransferase elevation and 2 for grade 3 pneumonitis. Both pneumonitis cases resolved following steroid treatment. Five patients (15%) discontinued nab-paclitaxel after completing the protocol-specified minimum of 4 cycles, owing to the following treatment-related AEs: grade 1 peripheral sensory neuropathy (n = 1), grade 2 asthenia (n = 1), grade 2 fatigue (n = 1), and peripheral neuropathy (n = 2; 1 each grade 2 and 3). No grade 5 AEs (all-cause or related to study treatment) occurred.
Clinical Activity
Median follow-up was 24.4 months (95% CI, 22.1-28.8 months). Table 3 summarizes the clinical activity of atezolizumab plus nab-paclitaxel. The ORR was 39.4% (95% CI, 22.9%-57.9%), with 1 CR and 12 PRs. The DCR was 51.5% (95% CI, 33.5%-69.2%). Responses were durable, with a median DOR of 9.1 months (range, 2.9-20.9 months). Six patients were treated beyond RECIST progression (4 with atezolizumab alone and 2 with combination treatment). Figure 2 shows change in tumor burden over time and Kaplan-Meier survival. The median PFS was 5.5 months (95% CI, 5.1-7.7 months), and the median OS was 14.7 months (10.1-not estimable).
Table 3. Summary of Atezolizumab Plus nab-Paclitaxel Clinical Activity.
| Responses | All Patients (N = 33) |
|---|---|
| Best confirmed response, No. (%) | |
| CR | 1 (3) |
| PR | 12 (36) |
| SD | 13 (39) |
| PD | 6 (18) |
| Missing/unevaluable | 1 (3) |
| Confirmed ORR, No. (%) [95% CI]a | 13 (39.4) [22.9-57.9] |
| Duration of confirmed response, median (range), mob | 9.1 (2.9-20.9)c |
| Median PFS (95% CI), mob,d | 5.5 (5.1-7.7) |
| Median OS (95% CI), mod | 14.7 (10.1-NE) |
Abbreviations: CR, complete response; NE, not estimable; PD, progressive disease; PFS, progression-free survival; PR, partial response; OS, overall survival; SD, stable disease.
Responses refer to either a (confirmed) CR or PR per Response Evaluation Criteria in Solid Tumors, version 1.1; 95% CIs for rates were constructed using the Clopper-Pearson method. Patients were classified as missing or unevaluable if no postbaseline response assessments were available or if all postbaseline assessments were unevaluable.
Responses per Response Evaluation Criteria in Solid Tumors, version 1.1.
Censored.
The 95% CIs for medians were constructed using the Brookmeyer-Crowley method.
Figure 2. Clinical Activity of Atezolizumab Plus nab-Paclitaxel.
A, Plot of tumor regression from baseline as measured by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in all evaluable patients (n = 32). Each bar represents an evaluable patient. B, Changes in tumor burden over time (n = 32). C, Kaplan-Meier estimate of RECIST progression-free survival (PFS) in the overall study population (N = 33). D, Kaplan-Meier estimate of overall survival (OS) in the overall study population (N = 33).
In exploratory subgroup analyses, clinical activity parameters were examined by line of therapy (1L vs 2L+) and PD-L1 status (PD-L1–positive defined as ≥1% of ICs expressing PD-L1, and PD-L1–negative defined as <1% of ICs expressing PD-L1). No statistically significant associations were found. The ORR was numerically higher in previously untreated patients vs previously treated patients (53.8% in 1L vs 30.0% in 2L+) and in PD-L1–positive vs PD-L1–negative patients (41.4% vs 33.3%) (eTable in Supplement 2). Median PFS was numerically longer in patients treated in the 1L vs 2L+ setting (8.6 vs 5.1 months; eTable in Supplement 2) and in patients who were PD-L1–positive vs PD-L1–negative (6.9 vs 5.1 months). Similarly, median OS was numerically longer in the 1L vs 2L+ setting (24.2 vs 12.4 months) and in patients who were PD-L1–positive vs PD-L1–negative (21.9 vs 11.4 months) (eTable in Supplement 2). The 1- and 2-year OS rates for patients treated in the 1L setting were 69.2% and 61.5%, respectively, vs 50.0% and 27.8% for patients treated in the 2L+ setting (eFigure 2 in Supplement 2).
Biomarker Analysis
Patients with preexisting adaptive immunity (elevated PD-L1 in the immune or tumor compartment and higher TILs or CD8+ T cells) were previously shown to have increased ORR and longer OS with atezolizumab monotherapy.10 Thus, these biomarkers were tested in the present combination study. Figure 1 outlines the number of baseline tissues evaluable from both the safety and serial biopsy cohorts for PD-L1 status, CD8+ T cells, and stromal TILs. The PD-L1 expression was more frequent on immune cells (12 of 24 patients, 50%) compared with tumor cells (4 of 24 patients, 17%). Lymphocytic infiltration was generally low, with a median TIL of 5% (range, 0%-60%) and appeared to be nonsignificantly elevated in tumors from patients treated in the 1L vs 2L+ setting (eFigure 3 in Supplement 2). There was no statistically significant association of baseline PD-L1 expression, TILs, or CD8+ T cells with clinical activity (eFigure 4 in Supplement 2).
A serial biopsy cohort of 25 patients was enrolled to evaluate the sequential effect of single-agent nab-paclitaxel followed by the combination of atezolizumab plus nab-paclitaxel on the tumor immune microenvironment. On-study biopsy and sample submission adherence was high: 25 patients submitted baseline samples, 24 patients post–nab-paclitaxel, and 21 patients post–atezolizumab plus nab-paclitaxel. However, not all samples were evaluable for every biomarker, resulting in significant attrition (Figure 1); 13 to 15 patients had evaluable pretreatment and post–nab-paclitaxel matched samples, and only 7 to 9 patients had evaluable samples at all 3 collection time points (Figure 1). No significant on-treatment changes vs baseline were observed in PD-L1 expressing immune cells, CD8+ T cells, or stromal TILs following exposure to nab-paclitaxel alone or after atezolizumab plus nab-paclitaxel (eFigure 5 in Supplement 2). No changes were associated with clinical response.
To test whether concurrent treatment with chemotherapy would dampen the immunostimulatory activity of atezolizumab, peripheral blood biomarkers known to be modulated by atezolizumab monotherapy were evaluated.20 Similar to the observations with single-agent atezolizumab, transient increases in activated proliferating CD8+ T cells (eg, CD8+, Ki-67+, HLA-DR+) and peripheral blood mononuclear cells CXCL10 RNA levels were observed at cycle 2, day 1 with the combination (eFigure 6 in Supplement 2). This suggests that the addition of nab-paclitaxel to immunotherapy is compatible with T-cell activation.
Discussion
In this phase 1b trial combining immune checkpoint blockade with chemotherapy in mTNBC, we report safety, clinical activity, and biomarker analyses for 33 patients who received atezolizumab plus nab-paclitaxel. Toxicity of the combination was manageable, and the safety profile was similar to that observed with atezolizumab or nab-paclitaxel alone, with the exception of the frequencies of neutropenia and pneumonitis.
The incidence of grade 3/4 neutropenia was 46% (n = 15) in this study, similar to the rate reported for nab-paclitaxel administered at a dose of 150 mg/m2 but numerically higher than that observed with a dose of 100 mg/m2 in the same study.39 Although a contribution from the combination with atezolizumab cannot be ruled out, the high rate of neutropenia may also be partly explained by the higher starting dose (125 vs 100 mg/m2).39 To mitigate the risk of excessive neutropenia, the starting nab-paclitaxel dose in the follow up phase 3 trial (IMpassion130; NCT02425891) was 100 mg/m2.40
Because of the potential for overlapping pulmonary toxicity with taxanes and immune checkpoint antibodies, pneumonitis cases were carefully monitored. Although the incidence and severity of pneumonitis was low in a large randomized trial testing atezolizumab plus taxane chemotherapy in non–small cell lung cancer,41 in this study, 3 patients (9%) experienced pneumonitis, a finding that requires follow-up in randomized trials.
Antitumor responses were observed in 39% (n = 13) of patients and were durable in several patients. In the 1L setting, the ORR was 53.8% and the median PFS was 8.6 months with the atezolizumab plus nab-paclitaxel combination, which compare favorably with historical trials of taxane therapy (ORR of 23% and median PFS of 5.4 months in a pooled analysis of 3 randomized phase 3 trials42; ORR of 35.6% and median PFS of 4.5 months in a phase 3 trial comparing carboplatin and docetaxel in unselected patients with advanced TNBC43), as well as atezolizumab monotherapy (ORR of 24%; median PFS of 1.6 months)10 in this setting. These preliminary findings warrant confirmation. Encouragingly, the phase 3 randomized trial (IMpassion130; NCT02425891) evaluating the atezolizumab plus nab-paclitaxel combination in patients with previously untreated mTNBC has recently reported positive findings.44
It is important to note that several patients experienced extended chemotherapy-free intervals and either received single-agent atezolizumab for more than 1 year (n = 5) or completely discontinued all study treatments, remaining disease free at the data cutoff without receiving additional anticancer therapy (n = 2). This finding could potentially be explained by a durable effect of atezolizumab but perhaps also by a readiness to stop chemotherapy early when a response was observed in the setting of immunotherapy. The ability to delay (or avoid) additional chemotherapy for a prolonged period in the metastatic setting is unusual in advanced TNBC; therefore, future trials of immunotherapy and chemotherapy combinations could assess the chemotherapy-free interval and its influence on patients’ quality of life.
Limitations
None of the tumor-based biomarkers examined were significantly associated with response or survival. Furthermore, correlative analyses did not show a clear contribution of nab-paclitaxel to the shaping of the tumor immune microenvironment, either on its own or in combination with atezolizumab. It is important to point out limitations, which included the heterogeneity of tumor tissues and patient population, the empirical selection of time points to interrogate changes in the tumor immune microenvironment, the biomarkers chosen, and the small number of evaluable serial tissue pairs.
Peripheral biomarker analyses indicated that nab-paclitaxel does not impair the transient CD8+ T-cell proliferation in peripheral blood described for single-agent atezolizumab,20 suggesting that chemotherapy may be compatible with atezolizumab-mediated immune responses. This is further supported by the finding of a transient but significant increase in the interferon-γ–mediated cytokine CXCL10 on cycle 2, day 1 (when compared with baseline), suggesting that nab-paclitaxel does not prevent atezolizumab-mediated T-cell activation.
Conclusions
In summary, in this phase 1b trial that combined immune checkpoint blockade with chemotherapy in the treatment of mTNBC, we observed a manageable toxicity profile as well as an antitumor activity signal, especially in the 1L setting. A randomized clinical trial is required to confirm these findings.
Trial Protocol
eTable 1. Summary of Atezolizumab Plus nab-Paclitaxel Clinical Activity by Line of Therapy and PD-L1 Expression
eFigure 1. Study Design and Schedule of Assessments
eFigure 2. Clinical Activity of Atezolizumab Plus nab-Paclitaxel by Line of Therapy
eFigure 3. Prevalence of Immune Biomarkers
eFigure 4. Tumor Immune Biomarkers and Survival
eFigure 5. Evaluation of Tumor Microenvironment Immune Biomarkers Upon nab-Paclitaxel and Atezolizumab Plus nab-Paclitaxel Exposure
eFigure 6. Tumor and Blood Pharmacodynamics
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eTable 1. Summary of Atezolizumab Plus nab-Paclitaxel Clinical Activity by Line of Therapy and PD-L1 Expression
eFigure 1. Study Design and Schedule of Assessments
eFigure 2. Clinical Activity of Atezolizumab Plus nab-Paclitaxel by Line of Therapy
eFigure 3. Prevalence of Immune Biomarkers
eFigure 4. Tumor Immune Biomarkers and Survival
eFigure 5. Evaluation of Tumor Microenvironment Immune Biomarkers Upon nab-Paclitaxel and Atezolizumab Plus nab-Paclitaxel Exposure
eFigure 6. Tumor and Blood Pharmacodynamics
Data Sharing Statement