Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Bintrafusp alfa; Cervical cancerBintrafusp alfa; Cáncer de cuello uterinoBintrafusp alfa; Càncer de coll uteríPurpose: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβ receptor II (a TGFβ “trap”) fused to a human IgG1 mAb blocking programmed death-ligand 1 (PD-L1), was evaluated as treatment in patients with locally advanced or persistent, recurrent, or metastatic (P/R/M) cervical cancer. Patients and Methods: In this multicenter, open-label, phase Ib trial (NCT04551950), patients with P/R/M cervical cancer received bintrafusp alfa 2,400 mg once every 3 weeks plus cisplatin or carboplatin plus paclitaxel with (Cohort 1A; n = 8) or without (Cohort 1B; n = 9) bevacizumab; patients with locally advanced cervical cancer received bintrafusp alfa 2,400 mg every 3 weeks plus cisplatin plus radiation, followed by bintrafusp alfa monotherapy maintenance (Cohort 2; n = 8). The primary endpoint was safety; secondary endpoints included efficacy (including objective response rate) and pharmacokinetics. Results: At the data cutoff of April 27, 2022, patients in Cohorts 1A, 1B, and 2 had received bintrafusp alfa for a median duration of 37.9, 31.1, and 16.7 weeks, respectively. Two dose-limiting toxicities (grade 4 amylase elevation and grade 3 menorrhagia) unrelated to bintrafusp alfa were observed in Cohort 1B and none in other cohorts. Most treatment-emergent adverse events of special interest were grades 1–2 in severity, most commonly anemia (62.5%–77.8%) and bleeding events (62.5%–77.8%). Objective response rate was 75.0% [95% confidence interval (CI), 34.9–96.8], 44.4% (95% CI, 13.7–78.8), and 62.5% (95% CI, 24.5–91.5) in Cohorts 1A, 1B, and 2, respectively. Conclusions: Bintrafusp alfa had manageable safety and demonstrated clinical activity, further supporting the investigation of TGFβ/PD-L1 inhibition in human papillomavirus–associated cancers, including cervical cancer.The authors thank the patients and their families, investigators, coinvestigators, and study teams at each of the participating centers and at the healthcare business of Merck KGaA, Darmstadt, Germany. Medical writing support was provided by Rebecca Yao, PhD, and Joyce Lee, PhD, of MediTech Media Asia Pacific, which was funded by the healthcare business of Merck KGaA (CrossRef Funder ID: 10.13039/100009945) and was previously part of an alliance between the healthcare business of Merck KGaA and GlaxoSmithKline, in accordance with Good Publication Practice (GPP 2022) guidelines (https://www.ismpp.org/gpp-2022). The trial was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and was previously part of an alliance between the healthcare business of Merck KGaA and GlaxoSmithKline. The healthcare business of Merck KGaA provided the trial drugs. The investigators worked with the healthcare business of Merck KGaA on the trial design, collection and analysis of data, and interpretation of results. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734

Advances in immunotherapy for cervical cancer

Cervical cancer; Immunotherapy; RadiotherapyCáncer de cuello uterino; Inmunoterapia; RadioterapiaCàncer de coll uterí; Immunoteràpia; RadioteràpiaCervical cancer still represents a major public health problem, being the fourth most common cancer in incidence and mortality in women worldwide. These figures are unacceptable since cervical cancer, an human papillomavirus-related malignancy, is a largely preventable disease by means of well-established screening and vaccination programs. Patients with recurrent, persistent, or metastatic disease unsuitable for curative therapeutic approaches represent a dismal prognosis population. Until recently, these patients were only candidates for cisplatin-based chemotherapy plus bevacizumab. However, the introduction of immune checkpoint inhibitors has revolutionized the treatment landscape of this disease achieving historical overall survival improvements in both the post-platinum and frontline settings. Interestingly, the clinical development of immunotherapy in cervical cancer is currently advancing to earlier stages of the disease, as the locally advanced setting, whose standard of care has not changed in the last decades with still modest outcomes. As more innovative immunotherapy approaches are in clinical early development in advanced cervical cancer, promising efficacy data are emerging that may shape the future of this disease. This review summarizes the main treatment advances carried out in the field of immunotherapy throughout the past years

Spatial Profiling of Ovarian Carcinoma and Tumor Microenvironment Evolution under Neoadjuvant Chemotherapy

Ovarian carcinoma; Tumor microenvironment; Neoadjuvant chemotherapyCarcinoma de ovario; Microambiente tumoral; Quimioterapia neoadyuvanteCarcinoma d'ovari; Microambient tumoral; Quimioteràpia neoadjuvantPurpose: This study investigates changes in CD8+ cells, CD8+/Foxp3 ratio, HLA I expression, and immune coregulator density at diagnosis and upon neoadjuvant chemotherapy (NACT), correlating changes with clinical outcomes. Experimental Design: Multiplexed immune profiling and cell clustering analysis were performed on paired matched ovarian cancer samples to characterize the immune tumor microenvironment (iTME) at diagnosis and under NACT in patients enrolled in the CHIVA trial (NCT01583322). Results: Several immune cell (IC) subsets and immune coregulators were quantified pre/post-NACT. At diagnosis, patients with higher CD8+ T cells and HLA I+-enriched tumors were associated with a better outcome. The CD8+/Foxp3+ ratio increased significantly post-NACT in favor of increased immune surveillance, and the influx of CD8+ T cells predicted better outcomes. Clustering analysis stratified pre-NACT tumors into four subsets: high Binf, enriched in B clusters; high Tinf and low Tinf, according to their CD8+ density; and desert clusters. At baseline, these clusters were not correlated with patient outcomes. Under NACT, tumors were segregated into three clusters: high BinfTinf, low Tinf, and desert. The high BinfTinf, more diverse in IC composition encompassing T, B, and NK cells, correlated with improved survival. PDL1 was rarely expressed, whereas TIM3, LAG3, and IDO1 were more prevalent. Conclusions: Several iTMEs exist during tumor evolution, and the NACT impact on iTME is heterogeneous. Clustering analysis of patients unravels several IC subsets within ovarian cancer and can guide future personalized approaches. Targeting different checkpoints such as TIM3, LAG3, and IDO1, more prevalent than PDL1, could more effectively harness antitumor immunity in this anti-PDL1–resistant malignancy.This work was supported by donations from patients and families through the “Parrainage Cancers Gynécologiques” Program and by the Association de Recherche Cancers Gynécologiques Research

Immune predictors of response to immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer

Biomarcador; Inhibidores del punto de control inmunitario; Microambiente tumoralBiomarcador; Inhibidors del punt de control immunitari; Microambient tumoralBiomarker; Immune checkpoint inhibitors; Tumor microenvironmentBackground Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking. Methods We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis. Results Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3). Conclusions These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.This research was supported by the Comprehensive Program of Cancer Immunotherapy & Immunology I (CAIMI-I) at the Vall d'Hebron Institute of Oncology, funded by the BBVA Foundation (grant 89/2017). Additional support was provided by the Programme Parrainage Chercheur at Institut Gustave Roussy

Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Purpose: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF beta receptor II (a TGF beta trap) fused to a human IgG1 mAb blocking programmed death-ligand 1 (PD-L1), was evaluated as treatment in patients with locally advanced or persistent, recurrent, or metastatic (P/R/M) cervical cancer.Patients and Methods: In this multicenter, open-label, phase Ib trial (NCT04551950), patients with P/R/M cervical cancer received bintrafusp alfa 2,400 mg once every 3 weeks plus cisplatin or carboplatin plus paclitaxel with (Cohort 1A; n = 8) or without (Cohort 1B; n = 9) bevacizumab; patients with locally advanced cervical cancer received bintrafusp alfa 2,400 mg every 3 weeks plus cisplatin plus radiation, followed by bintrafusp alfa monotherapy maintenance (Cohort 2; n = 8). The primary endpoint was safety; secondary endpoints included efficacy (including objective response rate) and pharmacokinetics.Results: At the data cutoff of April 27, 2022, patients in Cohorts 1A, 1B, and 2 had received bintrafusp alfa for a median duration of 37.9, 31.1, and 16.7 weeks, respectively. Two dose-limiting toxicities (grade 4 amylase elevation and grade 3 menorrhagia) unrelated to bintrafusp alfa were observed in Cohort 1B and none in other cohorts. Most treatment-emergent adverse events of special interest were grades 1-2 in severity, most commonly anemia (62.5%-77.8%) and bleeding events (62.5%-77.8%). Objective response rate was 75.0% [95% confidence interval (CI), 34.9-96.8], 44.4% (95% CI, 13.7-78.8), and 62.5% (95% CI, 24.5-91.5) in Cohorts 1A, 1B, and 2, respectively.Conclusions: Bintrafusp alfa had manageable safety and demonstrated clinical activity, further supporting the investigation of TGF beta/PD-L1 inhibition in human papillomavirus-associated cancers, including cervical cancer

Supplementary Table S1 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Table S1. Median duration of therapy. IQR, interquartile range; NA, not applicable.</p

Supplementary Methods S1 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Supplementary Methods</p

Supplementary Table S2 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Table S2. Study representativeness.</p