IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis.

BACKGROUND: Guidelines recommend atezolizumab plus nab-paclitaxel (A + nP) for first-line treatment of unresectable, locally advanced, or metastatic triple-negative breast cancer expressing programmed death-ligand 1 (PD-L1) on tumor-infiltrating immune cells (IC), based on IMpassion130. We report the final overall survival (OS) and safety of that study as per the prespecified analysis plan. PATIENTS AND METHODS: Patients were randomized to nP 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) with atezolizumab 840 mg (A + nP) or placebo (P + nP; days 1 and 15), until progression or unacceptable toxicity. Coprimary endpoints were progression-free survival [intention-to-treat (ITT) and PD-L1 IC-positive populations] and OS (tested hierarchically in the ITT population and, if significant, in the PD-L1 IC-positive population). RESULTS: Each arm comprised 451 patients; 666 (73.8%) had died by the final OS analysis cut-off (median follow-up, 18.8 months; interquartile range, 8.9-34.7 months). Median OS in the ITT population was 21.0 months [95% confidence interval (CI), 19.0-23.4 months] with A + nP, and 18.7 months (95% CI, 16.9-20.8 months) with P + nP [stratified hazard ratio (HR), 0.87; 95% CI, 0.75-1.02; P = 0.077]. Exploratory analysis in the PD-L1 IC-positive population showed a median OS of 25.4 months (95% CI, 19.6-30.7 months) with A + nP (n = 185) and 17.9 months (95% CI, 13.6-20.3 months) with P + nP (n = 184; stratified HR, 0.67; 95% CI, 0.53-0.86). Safety outcomes were consistent with previous analyses and the known toxicity profiles of each agent. Immune-mediated adverse events of special interest were reported in 58.7% and 41.6% of patients treated with A + nP and P + nP, respectively. CONCLUSION: Although the OS benefit in the ITT population was not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed with A + nP in PD-L1 IC-positive patients, consistent with prior interim analyses. This combination remained safe and tolerable with longer follow-up.

Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation.

Chronic lymphocytic leukemia (CLL), the most frequent form of adult leukemia in Western countries, is characterized by a highly variable clinical course. Expression profiling of a series of 160 CLL patients allowed interrogating the genes presumably playing a role in pathogenesis, relating the expression of functionally relevant signatures with the time to treatment. First, we identified genes relevant to the biology and prognosis of CLL to build a CLL disease-specific oligonucleotide microarray. Second, we hybridized a training series on the CLL-specific chip, generating a biology-based predictive model. Finally, this model was validated in a new CLL series. Clinical variability in CLL is related with the expression of two gene clusters, associated with B-cell receptor (BCR) signaling and mitogen-activated protein kinase (MAPK) activation, including nuclear factor-kappaB1 (NF-kappaB1). The expression of these clusters identifies three risk-score groups with treatment-free survival probabilities at 5 years of 83, 50 and 17%. This molecular predictor can be applied to early clinical stages of CLL. This signature is related to immunoglobulin variable region somatic hypermutation and surrogate markers. There is a molecular heterogeneity in CLL, dependent on the expression of genes defining BCR and MAPK/NF-kappaB clusters, which can be used to predict time to treatment in early clinical stages.