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

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

Supplementary Table S4 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Table S4. Pharmacokinetic exposure summary. AUC, area under the curve; Ceoi, concentration at end of infusion; Ctrough, concentration at the end of the dosing interval; CV, coefficient of variation; NA, not applicable; popPK, population pharmacokinetic; SD, standard deviation.</p

Supplementary Table S3 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Table S3. Serious treatment-related adverse events. Bleeding events: a One patient had two consecutive hematuria events, and another patient also had two events, the first episode related to bevacizumab, the second episode due to bintrafusp alfa. All hematuria events resolved within 4-6 weeks. b One patient treated with blood transfusion and vaginal tamponade, resolved within 2 days; other patient required blood transfusion and event resolved within 3 weeks. c Patient presented with bloody diarrhea and stomach discomfort, assessed as being caused by late radiation therapy and a rectal ulcer due to bevacizumab use; resolved with fasting and fluid replacement within 2 weeks. d Mucosal bleeding assessed as being caused by bintrafusp alfa and bevacizumab use; resolved with blood transfusion. e One event resolved with tumor compression by gauze and blood transfusion within a few days. f Bleeding in the duodenum resolved with standard gastrointestinal medication and fluid replacement within one week. g Rectal bleeding along with urinary tract infection; patient treated in emergency room with antibiotics and discontinuation of heparin for prior thrombosis, symptoms resolved within 2 weeks. AE, adverse event; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2.</p

Supplementary Figure S3 from Phase I Trial of First-line Bintrafusp Alfa in Patients with Locally Advanced or Persistent/Recurrent/Metastatic Cervical Cancer

Figure S3. Patient-level concentration profile of bintrafusp alfa at Day 1 postdose.</p