findings from a single-institution review of the incidence of immunotherapy-related toxicities in older patients with kidney cancer

Dr Ramnaraign on the Rationale for Examining irAEs in Older Patients With Kidney Cancer

Brian H. Ramnaraign, MD, assistant professor of medicine, Division of Hematology and Oncology, the University of Florida (UF) College of Medicine, UF Health, discusses findings from a single-institution review of the incidence of immunotherapy-related toxicities in older patients with kidney cancer.

At the 2023 International Kidney Cancer Symposium, Ramnaraign shared data from a retrospective study conducted at UF Health Cancer Center between January 2018 and September 2022. This investigation focused on the safety of immune checkpoint inhibitors in older patients with kidney cancer, and of the 58 patients included, the median age was 71 years (range, 65-92). Findings shared during the meeting showed that 57% of patients experienced immune-related adverse effects (irAEs). In patients where irAEs occurred, 15% were grade 1, 52% were grade 2, 30% were grade 3, and 3% were grade 4. Notably, no grade 5 irAEs were reported.

Additionally, 28% of all patients required steroids for the management of irAEs. These toxicities led treatment discontinuation in 12% of patients, and another 12% of patients had inpatient hospitalization due to irAEs. Overall, findings from the retrospective study suggest that immune checkpoint inhibitors are generally safe in older patients with kidney cancer, with low rates of serious irAEs, steroid use, hospitalization, and treatment discontinuation.

Ramnaraign highlgihts that this investigation focused on real-world outcomes for individuals aged 65 and above with kidney cancer who underwent treatment with these immune checkpoint inhibitors. He also highlighted that the motivation for this investigation stemmed from the underrepresentation of older patients in clinical trials, often due to factors such as polypharmacy, comorbidities, and age-related exclusion criteria.

To assess the safety data in these real-world scenarios, Ramnaraign says that he and investigators gathered information from their institution. Notably, the majority of these patients tolerated the treatment well, he emphasizes. The study indicates that most patients could continue treatment despite toxicity, with a minimal need for hospitalization or steroid use, Ramnaraign concludes.

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Brian H. Ramnaraign, MD, discusses findings from a single-institution review of the incidence of immunotherapy-related toxicities in older patients with kidney cancer.

Dr Ramnaraign on Retrospective Data For irAEs in Older Patients With Kidney Cancer

Brian Ramnaraign, MD, assistant professor of medicine, Division of Hematology and Oncology, University of Florida College of Medicine, discusses the investigation of atezolizumab (Tecentriq) with tivozanib (Fotivda) in castrate-resistant prostate cancer (CRPC).

The ongoing phase 1b/2 IMMCO-1 trial (NCT05000294) is examining the combination of atezolizumab with tivozanib in patients with unresectable or metastatic immunologically cold tumors, including CRPC previously treated with an androgen receptor inhibitor or cytotoxic chemotherapy in the advanced or metastatic setting, bile duct or gallbladder cancer, select hormone receptor–negative/HER2-positive breast cancers, ovarian cancer, pancreatic adenocarcinoma, soft tissue sarcoma, or vulvar cancer, who have received at least one prior systemic therapy in this setting.

CRPC is an immunologically cold tumor, and historical data have shown that patients with CRCP experienced an overall response rate of only 5% when treated with the PD-L1 inhibitor, pembrolizumab (Keytruda). Since VEGF inhibitor may enhance the effect of PD-(L)1–directed therapy, investigators are examining the use of the PD-L1 inhibitor atezolizumab in combination with the VEGF TKI tivozanib.

At the 2023 Genitourinary Cancers Symposium, investigators presented information on the IMMCO-1 study, which is trial in progress. Checkpoint inhibition has improved cancer outcomes in a variety of cancers, such as bladder cancer, kidney cancer, and lung cancer, Ramnaraign notes. However, checkpoint inhibitors don't work for all cancers, including many gastrointestinal cancers, Ramnaraign adds.

Investigators hypothesized that an immunologically cold tumor could be turned into a hot tumor by modulating the tumor microenvironment, recruiting a cytotoxic T lymphocytes, and changing the vascular permeability of tumors through the use of a VEGF TKI, Ramnaraign continues.

If investigators observe responses in patients enrolled in the basket study, the investigation could lead to a larger phase 2 clinical trial, Ramnaraign explains. Additionally, this trial could help patients by providing them with an additional line of therapy and allowing them to receive a checkpoint inhibitor, which is known to be a safe and efficacious option many patients with metastatic cancers, Ramnaraign concludes.

Brian Ramnaraign, MD, discusses the investigation of atezolizumab with tivozanib in castrate-resistant prostate cancer.

Dr. Ramnaraign on the Investigation of Atezolizumab Plus Tivozanib in CRPC

Brian Ramnaraign, MD, assistant professor of medicine, Division of Hematology and Oncology, University of Florida College of Medicine, discusses the evaluation of atezolizumab (Tecentriq) plus tivozanib (Fotivda) in a phase 1b/2 trial (NCT05000294) in patients with pancreatic, gallbladder, and bile duct cancers.

Based on findings from previous trials, the VEGF protein plays a key role in modulating antitumor responses; therefore, VEGF inhibition could potentially amplify the effects of checkpoint inhibitors in immunologically cold tumors, Ramnaraign says. Moreover, the combination of a VEGF TKI and an immune checkpoint inhibitor is already standard of care for patients with advanced kidney cancer and advanced endometrial cancer, Ramnaraign says.

Investigators designed the single-institution, single-arm, open label, phase 1b/2 study to examine the safety and efficacy of atezolizumab plus tivozanib in patients with immunologically cold tumors. The ongoing study is enrolling patients with metastatic pancreatic, gallbladder, biliary tract, ovarian, vulvar, castration-resistant prostate, and HER2-positive/hormone receptor–negative breast cancers, as well as patients with metastatic well-differentiated grade II or III neuroendocrine tumors and soft tissue sarcoma. Patients must have progressed on at least 1 line of systemic therapy.

Patients are not permitted to enroll if they have mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. These exclusion criteria are in place because these 3 biomarkers predict a response to checkpoint inhibitors, Ramnaraign explains. Patients are also not allowed to have received prior treatment with an immune checkpoint inhibitor or a VEGF TKI.

The phase 1b portion of the trial will evaluate the safety of atezolizumab plus tivozanib in a dose de-escalation design. Phase 2 portion of the study will enroll up to 26 additional patients using the recommended phase 2 dose identified in phase 1b. No unexpected toxicities have been reported thus far, and enrollment continues toward an upcoming preplanned interim analysis, Ramnaraign concludes.

Brian Ramnaraign, MD, discusses the evaluation of atezolizumab plus tivozanib in a phase 1b/2 trial in patients with pancreatic, gallbladder, and bile duct cancers.

Dr. Ramnaraign on the Evaluation of Atezolizumab Plus Tivozanib in GI Malignancies

Brian Ramnaraign, MD, assistant professor of medicine, Division of Hematology and Oncology, University of Florida College of Medicine, discusses sequencing immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations in metastatic renal cell carcinoma (mRCC).

When treating patients with mRCC, the preference of a patient and individual comorbidities must factor into therapy decisions, Ramnaraign says. There have been no head-to-head studies looking at the spanning treatment regimens in this space, and drawing conclusions from cross-trial comparisons should be done with a grain of salt, Ramnaraign adds.

When considering utilizing an IO combination compared with an IO and TKI combination, it is possible to begin with an IO and TKI combination in all risk categories, Ramnaraign continues. IO/TKI combinations have demonstrated higher objective response rates and cognitive load response across patients with varying levels of risk vs IO-IO combinations, Ramnaraign concludes.

Brian Ramnaraign, MD, discusses sequencing immunotherapy and tyrosine kinase inhibitor combinations in metastatic renal cell carcinoma.


Dr. Ramnaraign on Sequencing IO and TKI Combinations in Metastatic RCC

Brian Ramnaraign, MD, assistant professor of medicine, Division of Hematology and Oncology, University of Florida College of Medicine, discusses current first-line treatment guidelines for patients with metastatic renal cell carcinoma (RCC). 

Currently, many first-line treatment options are available for use in this patient population, according to Ramnaraign. When choosing among these approaches, is important to determine whether a patient has favorable-, intermediate-, or poor-risk disease, Ramnaraign says. 

There are 3 category 1 National Comprehensive Cancer Network recommendations for patients with favorable-risk disease, and 4 recommendations for those with intermediate- and poor-risk disease, Ramnaraign explains.

For patients with poor- or immediate-risk disease, possible treatment strategies include dual immunotherapy regimens or immunotherapies in combination with TKIs. For those with favorable-risk disease, immunotherapy/TKI combinations are often utilized, Ramnaraign concludes. 

Brian Ramnaraign, MD, discusses current first-line treatment guidelines for patients with metastatic renal cell carcinoma. 

Brian Ramnaraign, MD

Articles

Dr Ramnaraign on Retrospective Data For irAEs in Older Patients With Kidney Cancer

Dr. Ramnaraign on the Investigation of Atezolizumab Plus Tivozanib in CRPC

Dr. Ramnaraign on the Evaluation of Atezolizumab Plus Tivozanib in GI Malignancies

Dr. Ramnaraign on Sequencing IO and TKI Combinations in Metastatic RCC

Dr. Ramnaraign on Current Treatment Guidelines for First-Line Metastatic RCC