Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials

Abstract

Background: Patients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We investigated the activity and safety of nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma.

Methods: We did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0-1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. This study is ongoing although enrolment is closed. It is registered with ClinicalTrials.gov, number NCT02500797.

Findings: Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1-16] of 38 patients) in the nivolumab group and six (16% [7-30] of 38 patients) in the nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths.

Interpretation: Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomised study is warranted.

Funding: Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival.

Figure 1

CONSORT Diagram (Flow of Patients)

Figures 2A–B. Waterfall Plot for Best Response of Target Lesions/Nodes (RECIST v1·1)

Monotherapy (Figure 2A): The Waterfall Plots display the percent changed in the sum of the target lesions/nodes from study entry (vertical axis) for each patient (horizontal axis) during active treatment, for each arm. The two horizontal bars represent the criteria for PD (20% increase in tumor size) and response (30% decrease in tumor size for PR; total disappearance of target lesions/nodes for CR). The two patients noted as having an asterisk (‘*’) achieved PR according to radiographic assessments, yet are classified as PD by unequivocal PD on non-target lesions (as per RECIST v1·1 requirements). Combination Therapy (Figure 2B): The Waterfall Plots display the percent changed in the sum of the target lesions/nodes from study entry (vertical axis) for each patient (horizontal axis) during active treatment, for each arm. The two horizontal bars represent the criteria for PD (20% increase in tumor size) and response (30% decrease in tumor size for PR; total disappearance of target lesions/nodes for CR). The patient noted as having an asterisk (‘*’) achieved CR according to radiographic assessments, yet classified as PD by unequivocal PD. Four patients (noted by an “x” symbol) received combination therapy and did not have disease assessments following randomization. Three patients died and 1 patient had progressive disease in non-target lesions. Tumor growth was truncated to 100% for 2 patients having an increase of more than 100%, as noted by an “o” symbol.

Figures 2A–B. Waterfall Plot for Best Response of Target Lesions/Nodes (RECIST v1·1)

Monotherapy (Figure 2A): The Waterfall Plots display the percent changed in the sum of the target lesions/nodes from study entry (vertical axis) for each patient (horizontal axis) during active treatment, for each arm. The two horizontal bars represent the criteria for PD (20% increase in tumor size) and response (30% decrease in tumor size for PR; total disappearance of target lesions/nodes for CR). The two patients noted as having an asterisk (‘*’) achieved PR according to radiographic assessments, yet are classified as PD by unequivocal PD on non-target lesions (as per RECIST v1·1 requirements). Combination Therapy (Figure 2B): The Waterfall Plots display the percent changed in the sum of the target lesions/nodes from study entry (vertical axis) for each patient (horizontal axis) during active treatment, for each arm. The two horizontal bars represent the criteria for PD (20% increase in tumor size) and response (30% decrease in tumor size for PR; total disappearance of target lesions/nodes for CR). The patient noted as having an asterisk (‘*’) achieved CR according to radiographic assessments, yet classified as PD by unequivocal PD. Four patients (noted by an “x” symbol) received combination therapy and did not have disease assessments following randomization. Three patients died and 1 patient had progressive disease in non-target lesions. Tumor growth was truncated to 100% for 2 patients having an increase of more than 100%, as noted by an “o” symbol.

Figure 3A–B. Swimmer Plots for Assessments of Tumor Response, Over Time, by Patient

Monotherapy Figure 3A: The Swimmer Plots display a “swim lane” for each patient’s (vertical axis) initial treatment period (horizontal axis) and disease status, during treatment, and for each arm. Vertical lines identify the 6- and 12-week restaging. Red square symbols, either empty or solid, represent suspected and actual PD disease assessments. Patient’s having an initial progression within the first 12 weeks of treatment, may have a confirmatory 4-week evaluation (if meeting criteria for continuation treatment) showing either no PD or PD. In such cases, the patient’s first PD is used for study endpoints (represented by a solid red square symbol). Otherwise, the initial PD for the patient is indicated by an empty red square symbol and the patient may continue treatment. Patient’s having an arrow at the end of their swim lane continue to receive receiving protocol directed therapy at the time of data cut-off. Patient response is further noted by yellow/gold symbols appearing as rhombus (diamond) shape (PR = empty rhombus; CR = solid rhombus). Of note, one patient had 3 disease assessments within the first 12 weeks. This patient had confirmed PD (i.e., 2^nd PD), yet continued treatment an additional 3 weeks and subsequently ending due to a 3^rd PD. Combination therapy Figure 3A: The Swimmer Plots display a “swim lane” for each patient’s (vertical axis) initial treatment period (horizontal axis) and disease status, during treatment, and for each arm. Vertical lines identify the 6- and 12-week restaging. Red square symbols, either empty or solid, represent suspected and actual PD disease assessments. Patient’s having an initial progression within the first 12 weeks of treatment, may have a confirmatory 4-week evaluation (if meeting criteria for continuation treatment) showing either no PD or PD. In such cases, the patient’s first PD is used for study endpoints (represented by a solid red square symbol). Otherwise, the initial PD for the patient is indicated by an empty red square symbol and the patient may continue treatment. Patient’s having an arrow at the end of their swim lane continue to receive receiving protocol directed therapy at the time of data cut-off. Patient response is further noted by yellow/gold symbols appearing as rhombus (diamond) shape (PR = empty rhombus; CR = solid rhombus).

Figure 3A–B. Swimmer Plots for Assessments of Tumor Response, Over Time, by Patient

Monotherapy Figure 3A: The Swimmer Plots display a “swim lane” for each patient’s (vertical axis) initial treatment period (horizontal axis) and disease status, during treatment, and for each arm. Vertical lines identify the 6- and 12-week restaging. Red square symbols, either empty or solid, represent suspected and actual PD disease assessments. Patient’s having an initial progression within the first 12 weeks of treatment, may have a confirmatory 4-week evaluation (if meeting criteria for continuation treatment) showing either no PD or PD. In such cases, the patient’s first PD is used for study endpoints (represented by a solid red square symbol). Otherwise, the initial PD for the patient is indicated by an empty red square symbol and the patient may continue treatment. Patient’s having an arrow at the end of their swim lane continue to receive receiving protocol directed therapy at the time of data cut-off. Patient response is further noted by yellow/gold symbols appearing as rhombus (diamond) shape (PR = empty rhombus; CR = solid rhombus). Of note, one patient had 3 disease assessments within the first 12 weeks. This patient had confirmed PD (i.e., 2^nd PD), yet continued treatment an additional 3 weeks and subsequently ending due to a 3^rd PD. Combination therapy Figure 3A: The Swimmer Plots display a “swim lane” for each patient’s (vertical axis) initial treatment period (horizontal axis) and disease status, during treatment, and for each arm. Vertical lines identify the 6- and 12-week restaging. Red square symbols, either empty or solid, represent suspected and actual PD disease assessments. Patient’s having an initial progression within the first 12 weeks of treatment, may have a confirmatory 4-week evaluation (if meeting criteria for continuation treatment) showing either no PD or PD. In such cases, the patient’s first PD is used for study endpoints (represented by a solid red square symbol). Otherwise, the initial PD for the patient is indicated by an empty red square symbol and the patient may continue treatment. Patient’s having an arrow at the end of their swim lane continue to receive receiving protocol directed therapy at the time of data cut-off. Patient response is further noted by yellow/gold symbols appearing as rhombus (diamond) shape (PR = empty rhombus; CR = solid rhombus).

Figures 4A–B. PFS & OS Outcomes, by Treatment Arm

This figure displays the Kaplan-Meier estimates of the distribution of PFS and OS across time (in months), using one figure for each therapy. Patients who remain alive or without progression, are noted as censors and by a “+” symbol. The total number of patients at risk of an event, as well as the number of patients having an event (eg, deaths for OS) are noted over time and along the horizontal axis at key time points (eg, every 3 months from randomization). The vertical axis represents the percent of patients considered event free (ie, alive for OS) at a time point.

Figures 4A–B. PFS & OS Outcomes, by Treatment Arm

This figure displays the Kaplan-Meier estimates of the distribution of PFS and OS across time (in months), using one figure for each therapy. Patients who remain alive or without progression, are noted as censors and by a “+” symbol. The total number of patients at risk of an event, as well as the number of patients having an event (eg, deaths for OS) are noted over time and along the horizontal axis at key time points (eg, every 3 months from randomization). The vertical axis represents the percent of patients considered event free (ie, alive for OS) at a time point.