First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial [RNA-Seq]
ABSTRACT: While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
Project description:While patients with microsatellite instable, metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluates safety and efficacy of durvalumab plus tremelimumab in combination with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was primary objective of phase IB and no safety issue was observed. The primary objective of phase II was efficacy in terms of 3-month PFS in MSS patients, which was met with a 3 month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objective, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9–8.6] and overall survival was not reached in MSS patients. Higher tumor mutational burden and a lower degree of genomic instability in responder patients. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC.
Project description:<h4>Purpose</h4>This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer.<h4>Patients and methods</h4>Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFN? gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months.<h4>Results</h4>A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively.<h4>Conclusions</h4>Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFN? signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.
Project description:LESSONS LEARNED:Radioembolization with yttrium-90 resin microspheres can be combined safely with full doses of durvalumab and tremelimumab in patients with metastatic colorectal cancer. Regional radioembolization with yttrium-90 resin microspheres did not result in any hepatic or extrahepatic responses to a combination of durvalumab and tremelimumab. The lack of immunomodulatory responses to yttrium-90 on biopsies before and after treatment rules out a potential role for this strategy in converting a "cold tumor" into an "inflamed," immune responsive tumor. BACKGROUND:PD-1 inhibitors have been ineffective in microsatellite stable (MSS) metastatic colorectal cancer (CRC). Preclinical models suggest that radiation therapy may sensitize MSS CRC to PD-1 blockade. METHODS:Patients with MSS metastatic CRC with liver-predominant disease who progressed following at least one prior line of treatment were treated with yttrium-90 (Y90) radioembolization to the liver (SIR-Spheres; Sirtex, Woburn, MA) followed 2-3?weeks later by the combination of durvalumab and tremelimumab. A Simon two-stage design was implemented, with a planned expansion to 18 patients if at least one response was noted in the first nine patients. RESULTS:Nine patients enrolled in the first stage of the study, all with progressive disease (PD) during or after their first two cycles of treatment. Per preplanned design, the study was closed because of futility. No treatment-related grade 3 or greater toxicities were recorded. Correlative studies with tumor biopsies showed low levels of tumor-infiltrating lymphocyte (TIL) infiltration in tumor cancer islands before and after Y90 radioembolization. CONCLUSION:Y90 radioembolization can be added safely to durvalumab and tremelimumab but did not promote tumor-directed immune responses against liver-metastasized MSS CRC.
Project description:<h4>Importance</h4>Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H).<h4>Objective</h4>To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC.<h4>Design, setting, and participants</h4>A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease.<h4>Interventions</h4>We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio.<h4>Main outcomes and measures</h4>The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB).<h4>Results</h4>Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004).<h4>Conclusions and relevance</h4>This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted.<h4>Trial registration</h4>ClinicalTrials.gov Identifier: NCT02870920.
Project description:Background:5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy. Methods:This phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400?mg/m²)/5-fluorouracil (400?mg/m² as bolus followed by 2400?mg/m2 as a 46-hour infusion)/oxaliplatin (85?mg/m2) every 14 days with D (750?mg) D1 every 14 days and T (75?mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with ?=10%, ?=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.
Project description:BACKGROUND:Immune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes. Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns. Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation. METHODS:AtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8?cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12?months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee. DISCUSSION:The AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status. TRIAL REGISTRATION:AtezoTRIBE is registered at Clinicaltrials.gov ( NCT03721653 ), October 26th, 2018 and at EUDRACT (2017-000977-35), Februray 28th, 2017.
Project description:<b>Background: </b>Microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. However, a recent Japanese trial showed that regorafenib plus nivolumab had encouraging anti-cancer activity in MSS or pMMR mCRCs.<br><br><b>Materials and methods: </b>We retrospectively reviewed the efficacy and safety data of combination therapy with regorafenib plus anti-PD-1 antibody in patients with refractory MSS or pMMR mCRC in the medical centers of Shandong Province in China.<br><br><b>Results: </b>Twenty-three patients with MSS or pMMR mCRC received regorafenib plus anti-PD-1 antibody. Eighteen (78.3%) patients experienced stable disease as best response, five (21.7%) patients had progressive disease, and no partial response was observed. The disease control rate (DCR) was 78.3% (18/23), and the median progression-free survival (PFS) was 3.1 months (95% CI, 2.32-3.89). Four of five (80.0%) patients with progressive disease had baseline liver metastasis, while nine of 18 (50.0%) patients with stable disease displayed no liver metastasis. One patient receiving radiofrequency ablation treatment for liver and abdominal wall metastases prior to combination treatment experienced a remarkably prolonged PFS of 9.2 months with SD. Neither liver metastasis status nor previous exposure to regorafenib was associated with treatment outcome. Treatment-related grade 3 toxicities were observed in 5/23 (21.7%) patients.<br><br><b>Conclusion: </b>No objective response was observed with the combination of regorafenib plus anti-PD-1 antibody, suggesting its little clinical activity in unselected Chinese patients with pMMR/MSS mCRC. Meanwhile, it exhibited some potential benefit in this cohort in terms of DCR and PFS. Adverse events were generally tolerable and manageable. Prospective studies with large sample sizes are needed to verify the findings. This combination strategy plus local ablative therapy might be worthy of further exploration.
Project description:BACKGROUND:A single-arm phase II study of neoadjuvant chemotherapy plus durvalumab and tremelimumab in the treatment of advanced-stage ovarian cancer has begun in Korea. We hypothesized that adding durvalumab (anti-programmed death-ligand 1 antibody) and tremelimumab (anti-cytotoxic T-lymphocyte-associated protein 4 antibody) to chemotherapy in treating this cancer can increase progression-free survival (PFS) with minimal effects on safety. METHODS:During treatment, serial biopsies will be performed on pre-treatment, at interval debulking surgery and progression to identify immune biomarkers and changes in the tumor microenvironment. Patients with histologically confirmed stage IIIC/IV epithelial ovarian cancer are offered durvalumab, tremelimumab plus chemotherapy for neoadjuvant chemotherapy and durvalumab plus chemotherapy for adjuvant chemotherapy. Twenty-four patients will be included from four Korean institutions within 1 year. The primary endpoint is a 12-month PFS rate. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03899610.
Project description:<h4>Purpose</h4>Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.<h4>Patients and methods</h4>In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.<h4>Results</h4>We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9-26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0-27.0]. The median progression-free survival was 1.8 (95% CI, 1.7-1.9) months, median overall survival was 11.4 (95% CI, 10.1-17.4) months. Twenty five percent of patients (<i>n</i> = 6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8<sup>+</sup> T lymphocyte activation, differentiation, and proliferation in patients with objective response.<h4>Conclusions</h4>This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.
Project description:Importance:Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. Objective:To assess safety and objective response rate of durvalumab combined with tremelimumab. Design, Setting, and Participants:The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N?=?267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. Interventions:Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. Main Outcomes and Measures:Safety and tolerability and efficacy measured by objective response rate. Results:Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. Conclusions and Relevance:In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way. Trial Registration:clinicaltrials.gov Identifier: NCT02319044.