Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas

Abstract

Purpose: Outcomes for patients with advanced sarcomas are poor and there is a high unmet need to develop novel therapies. The purpose of this phase I study was to define the safety and efficacy of botensilimab (BOT), an Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody, plus balstilimab (BAL), an anti-PD-1 antibody, in advanced sarcomas.

Methods: BOT was administered intravenously (IV) at 1 mg/kg or 2 mg/kg once every 6 weeks in combination with BAL IV at 3 mg/kg once every 2 weeks for up to 2 years. The primary end point was to determine dose-limiting toxicities during the dose-escalation period. Secondary end points include objective response rate (ORR), duration of response (DOR), disease control rate, and progression-free survival (PFS) by RECIST 1.1. Exploratory end points include assessing patient biomarkers including tumor mutational burden, cytokines, and PD-L1 expression.

Results: Overall, 64 patients with sarcoma were treated; all were evaluable for safety and 52 for efficacy. The most common treatment-related adverse event (TRAE) was diarrhea/colitis occurring in 35.9% of patients, with grade 3 in 6.3% of patients. No grade 4 or 5 TRAEs were reported. For all evaluable patients, ORR was 19.2% (95% CI, 9.6 to 32.5), and 27.8% (95% CI, 9.7 to 53.5) for evaluable patients with angiosarcoma (n = 18); 33.3% in visceral and 22.2% in cutaneous subtypes. Median PFS for evaluable patients was 4.4 months (95% CI, 2.8 to 6.1), with a 6-month PFS rate of 36% (95% CI, 22 to 50) and a median DOR of 21.7 months (95% CI, 1.9 to not reached).

Conclusion: The combination of BOT/BAL demonstrated promising efficacy and safety in a large cohort of heavily pretreated sarcoma patients. This encouraging activity warrants further investigation (ClinicalTrials.gov identifier: NCT03860272).

FIG 1.

Flow diagram of the C-800-01 study and all treated patients with relapsed/refractory sarcomas (n = 64). BAL, balstilimab; BOT, botensilimab; SAS, safety analysis population.

FIG 2.

Clinical efficacy in efficacy-evaluable patients with sarcoma (n = 52). (A) Best overall response and (B) response over time. ^aA RECIST version 1.1-confirmed CR or PR. cAS, cutaneous angiosarcoma; CR, complete response; dLPS, dedifferentiated liposarcoma; LMS, leiomyosarcoma; PR, partial response; vAS, visceral angiosarcomas.

FIG 3.

Clinical outcomes in all efficacy-evaluable patients with sarcoma (n = 52) and efficacy-evaluable patients with angiosarcoma (n = 18). (A) PFS and (B) OS. OS, overall survival; PFS, progression-free survival.

FIG A1.

Algorithm for management of immune-mediated diarrhea/colitis. This algorithm reflects expert guidance and evolving literature on the management of immune-mediated colitis. It is intended to be used for patients receiving BOT-based therapy. This algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. ^aAlthough the CTCAE version 5.0 classifies and grades diarrhea and colitis as separate entities, in the clinical setting of ICI therapy for cancer, immune-related diarrhea and colitis occur along a common spectrum. Because there is an underlying common pathology, and inflammation often involves both the large and small intestines, immune-related diarrhea and colitis are considered and discussed jointly. ^bAssess patient as soon as possible with a goal of intervening within 24 hours of the onset of symptoms. The initial assessment may be over the phone or in person, but full workup requires in-person evaluation as soon as possible. Assessment should include number of stools above baseline, consistency (ie, watery), recent illnesses, infectious exposures, and recent antibiotics. Also assess for potential alarm symptoms (see 5 below). ^cCTCAEv5 grading: grade 1: increase of less than four stools per day over baseline; or mild increase in ostomy output over baseline. Grade 2: increase of four to six stools per day over baseline; or moderate increase in ostomy output over baseline; limiting instrumental ADLs. Grade 3: increase of ≥seven stools per day over baseline; or severe increase in ostomy output over baseline; limiting self-care ADLs; hospitalization indicated. Grade 4: life-threatening consequences, urgent intervention indicated. Grade 5: death. ^dIn a minority of patients treated with BOT, there is an early-onset, self-limited syndrome that may occur anywhere from hours to 1-2 weeks after infusion. This syndrome may include any of the following symptoms: fatigue, fever/chills, malaise, nausea, vomiting, or diarrhea. This syndrome does not represent immune-related diarrhea/colitis as it is generally self-limited and can be treated symptomatically with nonsteroidal anti-inflammatory drugs (consider 500 mg naproxen twice daily with appropriate GI prophylaxis if tolerated)/acetaminophen/±antimotility agents and supportive measures. Recommend careful monitoring of any patient who appears to have this syndrome to ensure resolution. The early-onset syndrome may reoccur with subsequent doses of BOT. However, if it did not occur with the first dose, it is unlikely to occur with subsequent doses and alternate etiologies should be considered, especially immune-related adverse events such as diarrhea/colitis. Timing of symptom onset in relation to BOT treatment is important. If diarrhea/nausea/vomiting occur >1-2 weeks after dosing, suspicion should be higher for immune-related diarrhea/colitis/enteritis and lower for the early-onset syndrome, whereas if symptoms develop within <1 week, immune-related diarrhea/colitis requiring steroids is extremely unlikely. ^eAny alarm symptom associated with diarrhea/colitis including but not limited to high-grade fever, severe abdominal pain, and blood in stool (hematochezia or melena) or hemodynamic instability warrant urgent evaluation. Note that fever may be seen with early-onset syndrome; however, this is a diagnosis of exclusion, especially if symptom onset is >1 week after dosing. ^fIf patient is unable to present for in-person evaluation in <24 hours, recommend utilization of oral prednisone that was provided at C1D1 (patient education and prescription) until they can present to medical facility for workup and treatment. For grade 1-2: prednisone 0.5-1 mg/kg/d. For grade 3-4: prednisone 1 mg/kg/d. ^gRecommend supportive measures immediately: BRAT diet and sufficient oral fluid intake, especially electrolyte-rich fluids. Ensure that any stool softeners and/or laxatives are discontinued. Antimotility agents are ineffective in the setting of immune-mediated diarrhea/colitis. ^hRecommend medical workup for acute-onset diarrhea of infectious or noninfectious etiology, which includes but is not limited to C. diff toxin, stool cultures, and ova/parasite examination, complete blood count, GI viral panel, complete metabolic panel, amylase/lipase, and inflammatory markers per provider discretion. C. diff is the most common alternate diagnosis and may co-occur with immune-related diarrhea/colitis. ⁱ If not already initiated, begin steroids. For grade 1-2: prednisone 0.5-1 mg/kg/d or equivalent. For grade 3-4: prednisone 1 mg/kg/d or equivalent, intravenous administration preferred if this would not result in a delay. ^jOnce patient has been assessed and nonimmune causes are effectively ruled out, we recommend treatment with infliximab (5 mg/kg) or equivalent, regardless of response to steroids or grade of diarrhea. Consider 10 mg/kg infliximab or equivalent for grade 4, or if severe hypoalbuminemia (albumin <2.5) is present. ^kIf tuberculosis testing (ie, Quantiferon Gold) is positive, then infliximab should not be given unless deemed acceptable by the treating provider on the basis of further workup and intervention, if the risk of anti-TNF is considered unacceptable, consider vedolizumab as an alternative. ^lRapid improvement of symptoms to grade 1 or less within 48 hours of treatment. If infliximab is administered and symptoms improve to ≤grade 1, a rapid steroid taper of <1 week is recommended. ^mIf steroid taper is rapid and in discussion with the sponsor, the plan is for the patient to resume BOT and administer three doses of infliximab in total according to the prescribing information (at 0, 2, and 6 weeks) regardless of symptom resolution. If steroid taper is rapid but there is no plan to resume BOT, then additional dosing of infliximab is based on clinical judgment. ⁿOnly patients who meet any of the following criteria will be considered eligible to restart BOT: (1) Diarrhea was not immune-mediated, or (2) did not exceed grade 2, responded rapidly to treatment, and received at least one dose of anti-TNF and will receive subsequent doses anti-TNF (total of at least three doses at 0, 2 and 6 weeks). Patients can restart BAL after discussion with sponsor even if diarrhea/colitis was grade 3 or higher, provided it was associated with BOT and not BAL monotherapy. ^oIf symptom duration requires a longer steroid taper, administer three doses infliximab total according to the prescribing information (at 0, 2, and 6 weeks). ^pIf symptoms do not improve within 48 hours after infliximab treatment, recommend re-evaluation for nonimmune causes of diarrhea and/or GI consultation for consideration of endoscopy. If immune-mediated etiology is still suspected, increase the dose of corticosteroids to a dose of 1-2 mg/kg/d prednisone or equivalent (ideally IV administered) and consider redosing infliximab at a higher dose (eg, 10 mg/kg). Consider treatment with vedolizumab (may require dosing by level if hypoalbuminemia present) or additional immunosuppressive therapy. abd, abdominal; ADL, activities of daily living; BOT/BAL, botensilimab/balstilimab; BRAT, bananas, rice, apple sauce, and toast; C. diff, clostridium difficile; CTCAEv5, Common Terminology Criteria for Adverse Events version 5; ICI, immune checkpoint inhibitor; IV, intravenously; TNF, tumor necrosis factor.

FIG A2.

Clinical efficacy in efficacy evaluable patients with angiosarcoma (n = 18). (A) Best overall response; (B) response over time. ^aA RECIST version 1.1-confirmed CR or PR. cAS, cutaneous angiosarcoma; CR, complete response; PR, partial response; vAS, visceral angiosarcomas.

FIG A3.

Time course showcasing an iRECIST responder. Imaging scans from a patient with visceral angiosarcoma who had pseudoprogression at 6 weeks (progressive disease by RECIST) followed by a deep partial response in a target lesion that has been maintained for 3 years and is now off therapy (for 2 years). iRECIST, modified RECIST for immune-based therapeutics.

FIG A4.

Evaluation of potential biomarkers of response to BOT and BAL treatment in patients with sarcoma. Comparison of OS of patients segregated by (A) peripheral IL-6 levels above or below the assay LLoQ; (B) combined positive score of PD-L1 expression above or below 1; and (C) germline FCGR3A p.V158F polymorphism. Data analyzed with log-rank (Mantel-Cox) test for P values and Mantel-Haenszel HR. (D) Summary data table of peripheral IL-6 levels 20, PD-L1 expression, TMB, and FCGR3A polymorphism (SNP) status. BAL, balstilimab; BOT, botensilimab; CPS, combined proportional score; HR, hazard ratio; IL, interleukin; LLOQ, lower limit of quantification; mut/Mb, mutations/megabase; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; SNP, single-nucleotide polymorphism; TMB, tumor mutational burden.