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The combination of durvalumab and tremelimumab demonstrated positive progression-free survival and overall survival rates with expected toxicity data in patients with advanced or metastatic soft tissue and bone sarcomas.
The combination of durvalumab (Imfinzi) and tremelimumab demonstrated positive progression-free survival (PFS) and overall survival (OS) rates with expected toxicity data in patients with advanced or metastatic soft tissue and bone sarcomas, according to findings from a phase 2 trial (NCT02815995) that were published in Lancet Oncology.
At a median follow-up of 37.2 months (interquartile range, 1.8-10.1), the 12-week PFS rate with the combination was 49% (95% CI, 36%-61%), with greater activity in certain histological sarcoma subtypes. The median PFS for the entire population was 2.8 months (95% CI, 1.8-6.4), the 12-month PFS rate was 28% (95% CI, 17%-40%), and the 24-month PFS rate was 15% (95% CI, 7%-26%).
“The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials,” lead study author Neeta Somaiah, MD, associate professor of Sarcoma Medical Oncology at The University of Texas MD Anderson Cancer Center, and colleagues, wrote.
Combinations of PD-1 and CTLA-4 inhibitors have previously improved efficacy in several cancer types. This single-center trial conducted at The University of Texas MD Anderson Cancer Center evaluated the efficacy, safety, and changes in the tumor microenvironment for durvalumab, a human IgG1 kappa monoclonal antibody that inhibits human PD-L1, plus tremelimumab, a human IgG2 monoclonal antibody that inhibits human CTLA-4, to collect correlative data on response and resistance to immune checkpoint inhibitors in multiple sarcoma subtypes.
The trial enrolled patients aged 18 years or older with histologically confirmed recurrent, advanced, or metastatic sarcoma and an ECOG performance status of 0 or 1 who had disease progression after at least 1 prior line of systemic therapy, if a standard therapy existed for their disease subtype. Patients needed to have measurable disease by RECIST v1.1 criteria, adequate organ function, and be willing to receive biopsies at baseline and during treatment for correlative studies if deemed safe by an experienced interventional radiologist.
Patients were excluded if they had received previous treatment with immune checkpoint inhibitors, if they had active autoimmune diseases within the past 2 years, if they had untreated central nervous system metastases, or if they had received treatment with systemic immunosuppressive medications within 14 days before the initiation of the study treatment. Additionally, treatment with any radiotherapy or systemic therapy was not allowed within 28 days before the initiation of treatment, and palliative radiotherapy needed to be completed at least 2 weeks before initiating treatment.
Sixty-two patients enrolled in the trial from August 17, 2016, to April 9, 2018. Fifty-seven (92%) patients received at least 1 dose of treatment and make up the intention-to-treat (ITT) population.
Eligible patients were segregated based on disease subtype: adipocytic tumors (including well-differentiated, dedifferentiated, myxoid, and pleomorphic liposarcomas); vascular tumors (including leiomyosarcomas and angiosarcomas); undifferentiated pleomorphic sarcomas; synovial sarcomas; osteosarcomas; and other sarcoma histologies. On February 27, 2017, alveolar soft-part sarcoma and chordomas were added to the trial as separate cohorts.
Patients received intravenous (IV) tremelimumab at 75 mg followed by IV durvalumab at 1500 mg approximately 1 hour later on day 1 of every 4-week cycle for 4 cycles. Thereafter, patients received durvalumab monotherapy every 4 weeks for a maximum of 8 additional cycles, until disease progression or unacceptable toxicity. Patients with disease progression were permitted to continue treatment at the discretion of the treating physician. Patients who received all 12 cycles of treatment entered surveillance and were allowed to consider retreatment at the same dose and regimen as the initial treatment plan if they progressed within 12 months of stopping therapy.
All patients received physical examinations during the screening phase and prior to each treatment cycle. Baseline magnetic resonance imaging scans or computed tomography scans were required within 30 days before the start of treatment. Investigators conducted the first restaging assessment at 8 weeks and a confirmatory scan at 12 weeks. Scans were completed every 8 weeks thereafter. Toxicity assessments, including hematology and a comprehensive metabolic panel, were conducted every 2 weeks for the first 4 months, and then every 4 weeks before each cycle until the end of treatment.
Additionally, biopsies of tumor tissue were done before the start of treatment, and a repeat biopsy was conducted 6 weeks after the start of treatment. Blood samples were taken at baseline, week 2, and week 6.
The primary end point of this trial was PFS at 12 weeks in the ITT population, defined as evidence of response or stable disease (SD) at 12 weeks after the start of treatment according to RECIST v1.1 criteria and immune-related RECIST (irRECIST) criteria, as assessed by central independent review. Concurrent measurements of response were evaluated by immune-related response criteria (irRC).
Secondary end points included overall response rate (ORR) per RECIST, irRC, and irRECIST with a confirmatory scan; safety and tolerability; median PFS, PFS at 12 months, and PFS at 24 months, defined as time from treatment initiation to disease progression by RECIST or death from any cause; and median OS, OS at 12 months, and OS at 24 months, defined as time from treatment initiation to death. All end points were assessed in each histological cohort.
At a data cutoff of April 30, 2020, 89% (n = 51) of patients in the ITT population had disease progression or had died. The median OS was 21.6 months (95% CI, 12.3-30.9), the 12-month OS rate was 65% (95% CI, 51%-76%), and the 24-month OS rate was 49% (95% CI, 35%-61%).
The ORR for all patients was 14% (n = 8). In the alveolar soft-part sarcoma cohort (n = 10), the ORR was 40% (n = 4; 95% CI, 12%-74%) by irRECIST and 50% (n = 5; 95% CI, 19%-81%) by irRC, the highest ORR rates of all the subtypes. Of this cohort, 20% (n = 2) patients achieved a complete response (CR) after completing therapy that persisted for more than 12 months on surveillance off-therapy. The 12-week PFS rate in the alveolar soft-part sarcoma cohort was 80% (95% CI, 41%-95%).
The investigators observed partial responses (PRs) by irRECIST in 20% (n = 1) of patients in each of the cutaneous angiosarcoma, undifferentiated pleomorphic sarcoma, and chordoma cohorts. PRs and CRs by irRC were observed in 50% (n = 5) of patients with alveolar soft-part sarcoma and in 20% (n = 1) of patients in each of the chordoma, undifferentiated pleomorphic sarcoma, and cutaneous angiosarcoma cohorts.
In total, 35% (n = 20; 95% CI, 23%-49%) of all patients had SD by irRECIST, and 32% (n = 18; 95% CI, 20%-45%) had SD by irRC. Twenty-two (39%) patients had progressive disease (PD) by irRECIST (95% CI, 26%-52%) and 23 (40%) had PD by irRC (95% CI, 28%-54%).
Of the ITT population, 25% (n = 14) completed all 12 cycles of treatment, including 60% (n = 6) of patients with alveolar soft-part sarcoma, 1 of whom restarted therapy upon progression during follow-up; 4 patients with chordoma; and 1 patient each with undifferentiated pleomorphic sarcoma, gastrointestinal stromal tumor, angiosarcoma, and synovial sarcoma.
In a post-hoc analysis, which grouped the cohorts by natural history, the 12-week PFS rate was 80% (95% CI, 50%-93%) for patients with indolent, chemoinsensitive cancers and 38% (95% CI, 24%-52%) for patients with chemosensitive cancers. The median PFS was 13.9 months (95% CI, 2.8-34.2) for the chemoinsensitive group and 1.8 months (95% CI, 1.8-3.2) for the chemosensitive group. The median OS was not reached (NR; 95% CI, 36.1 months-NR) in the chemoinsensitive group and 12.4 months (95% CI, 7.5-21.9) in the chemosensitive group.
Regarding safety, the toxicity profile of the combination was consistent with the known toxicity of CTLA-4 and PD-L1 inhibitors. A total of 60 treatment-related adverse effects (TRAEs), including 21 grade 3 to 4 TRAEs, were reported. The most common TRAEs of grade 3 or higher were increased lipase (7%; n = 4), colitis (5%; n = 3), and pneuomonitis (5%; n = 3).
In total, 16% (n = 9) of the ITT population had a treatment-related serious adverse effect (AE), the most frequent being colitis, which was reported in 5% (n = 3) of the population, as well as pneuomonitis, abdominal pain, diarrhea, dyspnea, anemia, myocarditis, headache, and lung infection. Additionally, 1 patient had grade 5 colitis and pneumonitis; this was the only death that occurred during treatment.
In total, 11% (n = 6) of patients discontinued treatment because of AEs, including 2 each with myocarditis, colitis, and pneuomonitis.
“This study provides the longest follow-up of patients with sarcoma treated with [an] immune checkpoint inhibitor combination targeting PD-L1 and CTLA-4. Particularly promising anti-tumor activity was seen in patients with alveolar soft-part sarcoma; future investigations are warranted in this disease subtype to assess the combination of anti-angiogenics with durvalumab and tremelimumab in a global randomized study,” the study authors concluded.
The completion of a phase 2 trial (NCT03141684) with atezolizumab (Tecentriq) plus bevacizumab (Avastin) vs atezolizumab alone in patients with advanced alveolar soft part sarcoma will help inform the optimal design and feasibility of a future randomized clinical trial.