“DKN-01 in Combination with Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish” by Samuel J Klempner et al
J Clin Oncol. (2024)
Key component: New novel IO combination approach: IO combinations beyond chemo and targeted therapies.
Abstract
Purpose: The outcomes of anti-PD-1 agents plus fluoropyrimidine/platinum in frontline advanced gastroesophageal adenocarcinomas (aGEAs) remain poor. We investigated the safety, tolerability, and activity of fluoropyrimidine/oxaliplatin and tislelizumab with the DKK1-neutralizing antibody DKN-01 in aGEAs in a phase IIa open-label study.
Patients and methods: Patients had untreated human epidermal growth factor receptor 2-negative aGEAs, RECIST v1.1 measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Patients received intravenous DKN-01 300 mg once every 2 weeks, tislelizumab 200 mg once every 3 weeks, oxaliplatin 130 mg/m2 once every 3 weeks, and capecitabine 1,000 mg/m2 twice daily on days 1-15 of each 21-day cycle. The primary end point was safety and tolerability. Key secondary end points included objective response rate (ORR) by RECISTv1.1, progression-free survival (PFS), and overall survival (OS).
Results: Between September 18, 2020, and April 8, 2021, 25 patients were enrolled. All patients who received at least one dose of DKN-01 were included in the safety analysis. Most patients had gastroesophageal junction tumors, median age was 61 years, 76% were male, and 55% were ECOG of 0. All patients reported at least one treatment-emergent adverse event. The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%.
Conclusion: DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801).
Why this matters: Combination immunotherapy is a key to further augment clinical responses with IO monotherapies and improve clinical benefit across tumor types. In this study the authors explored combining the DKK1-neutralizing antibody DKN-01 with tislelizumab and CAPOX chemotherapy in patients with HER2-negative advanced gastroesophageal adenocarcinoma. Results showed a promising objective response rate (ORR) of 73%, with progression-free survival (PFS) and overall survival (OS) of 11.3 and 19.5 months, respectively. DKN-01 was well-tolerated, with mainly mild gastrointestinal side effects and no skeletal-related events, despite DKK1’s involvement in bone remodeling. Notably, the therapy demonstrated effectiveness across PD-L1 expression levels, suggesting potential for broader application. Patients with high tumor DKK1 expression (48% of the cohort) responded well (90% ORR), indicating that DKN-01 may expand treatment benefits for aGEA patients beyond those with PD-L1–positive tumors. Limitations include the small sample size and single-arm design, but these initial findings support further investigation in ongoing trials.
“Final, 10Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma” by Jedd D Wolchok et al
N Engl J Med. (2024)
Key component: A decade with IO: Immunotherapy achieves long term durability in melanoma.
Abstract
Background: Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.
Methods: We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response.
Results: With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab.
Conclusions: The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
Why this matters: Durability is one of the most significant promises of immunotherapy, as some patients experience prolonged responses even after treatment ends. Results from Ten-year final outcomes of CheckMate 067 trial for untreated advanced melanoma further highlights the longterm durability that is achieved by immunotherapy. Patients were randomly assigned to receive nivolumab plus ipilimumab, nivolumab alone, or ipilimumab alone achieved highest median overall survival with the nivolumab plus ipilimumab combination (71.9 months), compared to nivolumab alone (36.9 months) and ipilimumab alone (19.9 months). Melanoma-specific survival exceeded 120 months for the combination, with 37% of these patients alive at the end of the trial. Among those alive and progression-free at 3 years, the 10-year melanoma-specific survival was 96% for nivolumab plus ipilimumab, 97% for nivolumab alone, and 88% for ipilimumab. These results confirm long-term survival benefits of nivolumab-based therapies over ipilimumab monotherapy for advanced melanoma.
"In vivo dendritic cell reprogramming for cancer immunotherapy” by Ervin Ascic et al
Science (2024)
Key component: Improving antigen presentation to augment systemic anti-tumor immune responses by in-vivo immune programming.
Abstract
Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells; induced tumor regressions; and established long-term systemic immunity in multiple mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy.
Why this matters: Dendritic cells play a key role in generating a systemic and durable anti-tumor immune response by cross presentation of tumor antigens to CD8+ T cells. In this study the authors developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced tumor regressions, and established long-term systemic immunity in syngeneic, xenografts mouse models and in human tumor spheroids. Reprogramming to immunogenic dendritic-like cells occurred irrespective of immune suppression. This study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy and presents a rationale to deliver transcription factors that enhance antigen presentation and T cell activation by intra-tumoral administration for in-vivo anti-tumor immune programming.
“15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1)” by J William Harbour et al
J Clin Oncol. (2024)
Key component: Validated and accurate prognostic testing is critical for precision medicine.
Abstract
Purpose: Validated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier.
Materials and methods: This study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS).RESULTS15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter.
Conclusion: In the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.
Why this matter: Identifying biomarkers to response or resistance is critical for success to cancer immunotherapy. Although it is appealing to identify a specific biomarker that can predict therapeutic benefit, however this is rarely possible in clinical setting other than tumor with genetic mutations. This study by Harbor et al. aimed to validate a prognostic test for uveal melanoma (UM) by integrating a 15-gene expression profile (15-GEP) with PRAME RNA expression and examining whether certain clinical factors could improve its accuracy. A total of 1,577 UM patients from North American centers were assessed using this integrated classifier. The key outcome measured was metastasis-free survival (MFS). Results showed that patients with the 15-GEP class 1/PRAME-negative profile had the highest five-year MFS rate (95.6%), while those with class 2/PRAME-positive had the lowest (44.8%). The 15-GEP classification was found to be the most critical predictor of MFS, followed by PRAME status. Tumor diameter was the only clinical factor that added prognostic value. In conclusion, this study validated the superior accuracy of combining the 15-GEP and PRAME classifier for predicting metastasis risk in UM, highlighting its potential for enhancing surveillance and treatment planning.