CONTACT-01: A Randomized Phase III Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy.

PURPOSE: Although checkpoint inhibitors have improved first-line treatment for non-small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti-PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti-PD-L1/PD-1 and platinum-containing chemotherapy. METHODS: This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m2 intravenously once every 3 weeks. The primary end point was overall survival (OS). RESULTS: One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively). CONCLUSION: Atezolizumab plus cabozantinib after disease progression following anti-PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.

Extension of the Alternative Intravenous Dosing Regimens of Atezolizumab into Combination Settings through Modeling and Simulation.

Atezolizumab is approved as an intravenous (IV) infusion for use as a single agent and in combination with other therapies in a number of indications. The objectives of this publication are to characterize atezolizumab pharmacokinetics (PK) across indications with the available clinical data from one phase I and eight phase III studies, to determine the exposure-response (ER) relationships in combination settings across a variety of tumor types, and to provide the clinical safety to support the extension of the 840 mg q2w, 1200 mg q3w, and 1680 mg q4w IV dosing regimens across various indications in combination settings. Across all clinical studies, atezolizumab PK remained in the dose-linear range and were similar across tumor types when used in combination therapy or as a monotherapy. In the combination studies, efficacy was independent of the exposures tested and there was no significant increase in adverse events with increasing atezolizumab exposure (flat ER). The safety profile of atezolizumab in the individual combination studies was generally consistent with the established safety profile of atezolizumab, the combination partners, and the disease under study. The similar atezolizumab PK across monotherapy and combination therapy settings as well as the flat ER in new tumor types and combination therapies support the use of the 3 interchangeable atezolizumab dosing regimens in the combination setting. Atezolizumab is now approved with 3 interchangeable IV dosing regimens of 840 mg q2w, 1200 mg q3w, and 1680 mg q4w for single-agent and combination therapy use in the USA and EU.

Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial.

PURPOSE: Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS: Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)-positive populations. RESULTS: At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference -0.33%; 95% CI, -9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1-positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference -8.26%; 95% CI, -20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION: Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide-paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1-positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial.

INTRODUCTION: Cytotoxic agents have immunomodulatory effects, providing a rationale for combining atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1]) with chemotherapy. The randomized phase III IMpower131 study (NCT02367794) evaluated atezolizumab with platinum-based chemotherapy in stage IV squamous NSCLC. METHODS: A total of 1021 patients were randomized 1:1:1 to receive atezolizumab+carboplatin+paclitaxel (A+CP) (n = 338), atezolizumab+carboplatin+nab-paclitaxel (A+CnP) (n = 343), or carboplatin+nab-paclitaxel (CnP) (n = 340) for four or six 21-day cycles; patients randomized to the A+CP or A+CnP arms received atezolizumab maintenance therapy until progressive disease or loss of clinical benefit. The coprimary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population. The secondary end points included PFS and OS in PD-L1 subgroups and safety. The primary PFS (January 22, 2018) and final OS (October 3, 2018) for A+CnP versus CnP are reported. RESULTS: PFS improvement with A+CnP versus CnP was seen in the ITT population (median, 6.3 versus 5.6 mo; hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.60-0.85; p = 0.0001). Median OS in the ITT population was 14.2 and 13.5 months in the A+CnP and CnP arms (HR = 0.88, 95% CI: 0.73-1.05; p = 0.16), not reaching statistical significance. OS improvement with A+CnP versus CnP was observed in the PD-L1-high subgroup (HR = 0.48, 95% CI: 0.29-0.81), despite not being formally tested. Treatment-related grade 3 and 4 adverse events and serious adverse events occurred in 68.0% and 47.9% (A+CnP) and 57.5% and 28.7% (CnP) of patients, respectively. CONCLUSIONS: Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms.

The do's and don'ts of p53 isoforms.

Upon DNA damage and other stresses, the transcription factor p53 elicits numerous responses including DNA repair, cell cycle arrest and apoptosis, properties that make p53 the prototype tumor suppressor. In addition, p53 also transactivates genes whose products act in an anti-apoptotic manner providing strong evidence that p53 exhibits both tumor suppressive and tumorigenic functions. Although several events were postulated to contribute to the p53-mediated decision process, the precise mechanism(s) that governs p53 activities is still elusive. Recently, it was found that the p53 gene allows expression of at least nine different isoforms that arise from multiple splicing events and the usage of alternative promoters. Several of these isoforms were shown to critically interfere with the function of the full-length p53 mainly by acting in a dominant-negative manner. However, an isoform-dependent selective activation of p53 target genes was also observed. Furthermore, certain p53 isoforms are aberrantly expressed in various tumors strongly implying their involvement in tumorigenic events. Thus, p53 isoforms may represent crucial determinants in p53-mediated decision processes whose precise functions (their do's and don'ts) are only beginning to emerge.

Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells.

The intracellular pathways leading to mitochondrial activation and subsequent cell death in the ceramide-mediated stress response have been intensively studied in recent years. Experimental evidence has been provided that ceramide-induced apoptosis is inhibited by overexpression of antiapoptotic proteins of the Bcl-2 family. However, the direct effect of proapoptotic gene products, e.g. Bax, on ceramide-induced death signalling has not yet been studied in detail. In the present work, we show by measurement of mitochondrial permeability transition, cytochrome c release, activation of caspase-3 and DNA fragmentation that ceramide-induced apoptosis is marginal in Bax-negative DU 145 cells. Reconstitution of Bax by generation of DU 145 cells stably expressing this proapoptotic factor, clearly enhanced ceramide-induced apoptosis at all levels of the mitochondrial signalling cascade. Using the broad-range caspase inhibitor zVAD-fmk and zDEVD-fmk, an inhibitor of caspase-3-like activities, we demonstrate that the ceramide-induced mitochondrial activation in Bax-transfected DU 145 cells is caspase-independent. On the other hand, apoptotic events located downstream of the mitochondria, e.g. DNA fragmentation, were shown to be caspase-dependent. This influence of Bax on ceramide-induced apoptosis was confirmed in another cellular system: whereas Bax-positive HCT116 wild type cells were very sensitive towards induction of cell death by C(2)-ceramide, sensitivity of Bax knock-out HCT116 cells was significantly reduced. Thus, we conclude that Bax is a key activator of ceramide-mediated death pathways.

Functional characterization of p53beta and p53gamma, two isoforms of the tumor suppressor p53.

The p53 gene encodes several isoforms that can interfere with stress responses by modulating p53 wild-type (wt) function. Recently, a C-terminally truncated splice variant, p53beta, has been implicated in the regulation of p53-dependent apoptosis, whereas the function of similarly spliced p53gamma was not investigated before. Therefore, we studied the impact of these isoforms on the function of endogenous p53wt and compared it with that of exogenously expressed p53wt. We demonstrate that despite an efficient nuclear expression of all isoforms, only p53wt modulates apoptosis induction. Furthermore, only p53wt assembles into a transcription-competent oligomeric complex or translocates to mitochondria upon stress induction. Both C-terminally truncated isoforms fail to modulate the apoptotic function of p53wt because they are unable to associate with p53wt and hence do not bind to p53 DNA recognition sequences. Consistently, the dominant-negative function of transactivation-deficient Delta133p53 is completely lost in the Delta133p53beta variant. Intriguingly, the alternatively spliced C-terminus protects p53beta and p53gamma not only from MDM2-mediated proteasomal degradation, but strongly impairs their binding to this negative regulator. Thus, our data demonstrate the necessity of the regularly spliced C-terminal tail for multiple layers of p53 regulation and function.

Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway.

Nbk/Bik (natural born killer/Bcl-2-interacting killer) is a tissue-specific BH3-only protein whose molecular function is still largely unknown. To investigate the mechanism of Nbk action, we established a single- vector adenoviral system based on the Tet-off conditional expression of Nbk. Upon Nbk expression, only Bax-positive, but not Bax-deficient cells were found to undergo apoptosis. Interestingly, Nbk failed to induce apoptosis in the absence of Bax, even despite expression of the related molecule Bak. Re-expression of Bax restored the sensitivity to Nbk. Similarly, Bax wild-type HCT116 cells were highly susceptible, whereas HCT116 Bax knock-out cells remained resistant to Nbk-induced apoptosis. In Bax-positive cells, Nbk induced a conformational switch in the Bax N-terminus coinciding with cytochrome c release, mitochondrial permeability transition and caspase-9 processing. Immunoprecipitation studies revealed that Nbk interacts with Bcl-x(L) and Bcl-2 but not with Bax. Since, in addition, Nbk did not localize to the mitochondria, our data suggest a model in which Nbk acts as an indirect killer to trigger Bax-dependent apoptosis, whereas Bak is not sufficient to confer sensitivity to Nbk.