Dr Singer on Toxicities Associated With First-Line IO/TKI Regimens in RCC

“In general, we see higher rates of AEs with [IO/TKI regimens], and that’s just for the TKI component—when you add in the immunotherapy component, the AEs observed with nivolumab or pembrolizumab are [similar to what is seen when] these drugs are used [in] any cancer.”

Adam E. Singer, MD, PhD, Health Sciences Clinical Instructor, medicine, division lead, kidney cancer, Division of Hematology/Oncology, UCLA Health, discusses how the safety profiles of nivolumab (Opdivo) and cabozantinib (Cabometyx) compare with those of immuno-oncology (IO)/TKI regimens in first-line renal cell carcinoma (RCC).

The adverse effect (AE) profiles of VEGF TKIs, such as axitinib (Inlyta), lenvatinib (Lenvima), and cabozantinib, are generally similar, though axitinib tends to be associated with fewer AEs compared with lenvatinib or cabozantinib, Singer begins. These AEs result from VEGF inhibition and off-target kinase effects, according to Singer. Commonly observed AEs include diarrhea, nausea, anorexia, hypertension, and fatigue, he lists. Hypothyroidism, proteinuria, and dysphonia are also reported; hand-foot syndrome is more frequently associated with cabozantinib than the other agents, Singer notes.

Although AE rates are high with TKIs alone, their use in combination with immune checkpoint inhibitors like nivolumab or pembrolizumab (Keytruda) introduces additional AEs associated with immunotherapy, Singer continues. Immune-mediated AEs include thyroid dysfunction, pruritus, and diarrhea, among others, which are consistent with these agents’ well-characterized profiles in various cancers, he details.

The combination of TKIs with immunotherapy can lead to overlapping toxicities that require close monitoring and individualized management strategies, Singer notes. For instance, although diarrhea is common to both TKIs and immunotherapy, its underlying cause may differ, necessitating distinct interventions, Singer explains. Similarly, immune-mediated AEs, such as colitis or hepatitis, may require immunosuppressive treatments, complicating care when combined with the toxicities from TKIs, he adds. Overall, the continued characterization of these AE profiles will inform strategies to minimize their effect on quality of life and ensure sustained adherence to treatment for patients with RCC, Singer concludes.

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Adam E. Singer, MD, PhD, discusses the safety profiles of immuno-oncology/TKI regimens in first-line renal cell carcinoma.

Dr Singer on the Efficacy of IO/TKI Doublets in Advanced RCC

Adam E. Singer, MD, PhD, Health Sciences Clinical Instructor, medicine, division lead, kidney cancer, Division of Hematology/Oncology, UCLA Health, discusses currently available combination treatment regimens for the first-line treatment of patients with renal cell carcinoma (RCC), highlighting key findings from the phase 3 CheckMate 9ER trial (NCT03141177) investigating nivolumab (Opdivo) plus cabozantinib (Cabometyx) in patients with advanced RCC.

In the frontline treatment of patients with RCC, multiple VEGFR/TKI and checkpoint inhibitor combinations are available, offering improved tolerability over traditional monotherapies, such as sunitinib (Sutent), Singer begins. Three prominent IO/TKI combinations include axitinib (Inlyta) plus pembrolizumab (Keytruda), cabozantinib plus nivolumab, and lenvatinib (Lenvima) plus pembrolizumab, he says. Additionally, dual checkpoint inhibition with ipilimumab (Yervoy) plus nivolumab is approved for this patient population.

Data from the CheckMate 9ER trial, which were presented at the 

, showed that patients who received cabozantinib plus nivolumab stayed on therapy for a longer duration than those who received sunitinib monotherapy, reflecting the improved safety profile of the combination regimen, Singer explains. The 48-month mean time on protocol treatment among patients with grade 2 or higher treatment-related adverse effects (TRAEs) was 8.3 months in the combination arm vs 6.7 months in the sunitinib monotherapy arm (difference, 1.7; 95% CI, 0.1-3.2). These respective values among patients without grade 2 or higher TRAEs were 14.3 months and 7.4 months (difference, 6.8; 95% CI, 4.8-8.8).

Moreover, patients who discontinued cabozantinib plus nivolumab generally delayed the initiation of a subsequent therapy for a longer duration than those who discontinued sunitinib, indicating a post-discontinuation benefit with the combination, he notes. At 48 months of follow-up, the mean treatment-free survival (TFS) post–study treatment in patients without grade 2 or higher TRAEs was 3.0 months in the combination arm vs 2.3 months in the sunitinib arm (difference, 0.7; 95% CI, –0.4 to 1.8). In these respective populations, the mean TFS in those with grade 2 or higher TRAEs was 3.9 months vs 2.3 months (difference, 1.6; 95% CI, 0.5-2.8). This effect may stem from the extended half-lives of immunotherapies, which potentially offer prolonged efficacy even after treatment cessation, Singer concludes.

Adam E. Singer, MD, PhD, discusses currently available combination treatment regimens for the first-line treatment of patients with renal cell carcinoma.

Dr Singer on the Lack of Clinical Benefit for Immunotherapy Rechallenge in Advanced RCC

Adam Singer, MD, PhD, health sciences clinical instructor of medicine, division lead, Kidney Cancer, Division of Hematology/Oncology, University of California Los Angeles Health, discusses data for immunotherapy rechallenge in patients with advanced renal cell carcinoma (RCC) who have experienced disease progression on prior immunotherapy.

Singer notes that data are now available from 2 large phase 3 studies showing a lack of benefit from rechallenging with immunotherapy in patients who have previously been exposed to one of these agents. The first study to assess this approached was 

the phase 3 CONTACT-03 trial (NCT04338269)

, which randomly assigned patients with previously treated advanced RCC to receive cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) or cabozantinib alone.

 demonstrated no significant difference in progression-free survival (PFS) or overall survival (OS) between the two arms. Patients in the atezolizumab arm experienced a PFS of 10.6 months (95% CI, 9.8-12.3) compared with 10.8 months (95% CI, 10.0-12.5) in those given cabozantinib alone (HR, 1.03; 95% CI, 0.83-1.28; 

 = .78). The median OS was 25.7 months (95% CI, 21.5–not evaluable [NE]) in the experimental arm vs NE (95% CI, 21.1-NE) in the control arm (HR, 0.94; 95% CI, 0.70-1.27; 

 randomly assigned patients to receive tivozanib (Fotivda) plus nivolumab (Opdivo) or tivozanib alone. 

 showed that the median PFS was 5.7 months (95% CI, 4.0-7.4) for the combination vs 7.4 months (95% CI, 5.6-9.2) for tivozanib alone (HR, 1.10; 95% CI, 0.84-1.43; 

The findings from these phase 3 trials collectively demonstrate the ineffectiveness of sequential immunotherapy in advanced RCC, highlighting the need for alternative therapeutic strategies, Singer says. He advises that these data should guide clinical decision-making, recommending against the use of immunotherapy after progression on prior immunotherapy due to the lack of benefit and added toxicity, he concludes.

Adam Singer, MD, PhD, discusses the lack of clinical benefit for sequential immunotherapy in advanced renal cell carcinoma.

Neutropenic fever, a commonly occurring and potentially serious chemotherapy complication, requires careful monitoring and close observation. Neutropenia affects a significant number of patients undergoing chemotherapy, with about half experiencing some level of neutropenia, according to the American Society of Clinical Oncology.

 Neutropenic patients are inherently at risk for developing neutropenic fever, which confers an increased risk of mortality, estimated to be at least 15% higher than in those who do not experience neutropenic fever.

Early detection and prompt treatment of neutropenic fever are essential for effective management, but the conventional approach of using spot-check thermometers has innate limitations. Despite technological advancements, the fundamental process of using a thermometer has remained largely unchanged: patients are still instructed to check their temperature when symptoms arise or a few times per day. However, neutropenic fever can sometimes occur without symptoms or during non-waking hours, which means spot checks likely miss some episodes.

Unlike traditional thermometers, remote patient monitoring (RPM) offers a novel, modernized approach for detecting and monitoring neutropenic fever by enabling continuous temperature monitoring and more timely intervention. RPM devices represent a convenient, technology-based solution that can provide peace of mind in managing a potentially serious condition.

Advancing Health Care With Wearable Technology

RPM devices such as automated temperature monitors have the potential to bring about a significant shift in how health data are collected. Rather than patients or study participants having to take action with a traditional thermometer, they simply wear a small, unobtrusive wireless patch throughout their day and even during sleep. The device continuously transmits temperature data to secure, HIPAA-compliant remote servers. This innovative approach can not only streamline patient care but also holds promise for decentralizing data collection in studies.

Researchers are conducting a prospective study involving 80 patients with cancer who are receiving outpatient chemotherapy treatment. The study utilizes 

Vivalink’s continuous temperature monitor

—a clinical-grade wearable thermometer that automatically checks patients’ body temperature every 10 minutes. The study specifically focuses on patients with breast cancer, colon cancer, lung cancer, or one of two common types of non-Hodgkin lymphoma who are undergoing TC (docetaxel plus cyclophosphamide), mFOLFOX6 (leucovorin, fluorouracil, plus oxaliplatin), cisplatin/pemetrexed, or R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine plus prednisone) chemotherapy regimens.

Study participants will wear a Vivalink temperature monitor continuously during the initial 3 months of chemotherapy treatment. If a fever is detected, real-time notifications will be sent via email to both patients and their treating oncologists. For each fever episode, the system will generate two emails: one notifying that a fever has occurred, and another reporting the maximum temperature during the episode. Patients will subsequently undergo blood tests to confirm neutropenia.

The study seeks to determine the occurrence rate of neutropenic fever in patients undergoing common chemotherapy regimens and to enable earlier detection and treatment of neutropenic fever compared with spot-check thermometers. Additionally, the study intends to evaluate the morbidity, mortality, health care utilization, and cost of care of patients with neutropenic fever detected through automated temperature patches.

Understanding Neutropenic Fever With Wearables

Over the past few decades, extensive research has been conducted on the rates of neutropenic fever associated with various chemotherapy regimens. These studies helped inform guidelines that now separate chemotherapy regimens into different risk categories: high risk (>20% incidence) and intermediate risk (10%-20% incidence) of causing neutropenic fever.3 The guidelines also recommend the use or consideration of myeloid growth factors, which are medications administered alongside each chemotherapy cycle to boost white blood cell counts and reduce the risk of neutropenic fever. These guidelines not only shape medical practice but also impact insurance coverage decisions.

However, since all of these studies used traditional manual temperature readings to detect fevers, they faced the same limitations as using spot-check thermometers in clinical practice. As a result, there is a possibility that the actual incidence of neutropenic fever is higher than previously estimated. This could have significant implications in two ways:

Intermediate risk chemotherapy regimens may have a higher risk of neutropenic fever than previously believed. The potential reclassification as high risk could result in revisions to guideline recommendations and insurance reimbursement policies for myeloid growth factors.

Wearable technology can identify cases of neutropenic fever that may have otherwise gone unnoticed, revealing a previously unrecognized category of patients with neutropenic fever who may be able to safely forgo treatment.

The use of wearable technology for fever detection has the potential to advance our understanding of neutropenic fever and its related risk categories. While the primary objective of this study is not to formally establish criteria for "low risk" neutropenic fever, it may be able to generate valuable hypotheses regarding the characteristics of such a syndrome.

Neutropenic fever itself contributes to around 5% of all cancer-related hospitalizations and accounts for approximately 8% of the total costs associated with these hospitalizations.

 When it is safe to do so, managing patients with neutropenic fever outside of the hospital can enhance patient care and alleviate the burden on existing health care resources.

Unlocking Insights With Remote Patient Care in Oncology

The aforementioned study will monitor temperature only, but remote monitoring of other vital signs can offer valuable real-time health insights for patients with cancer who are at high risk of treatment-related complications. RPM devices have the capability to collect vast amounts of data in real-world situations, providing a comprehensive picture of a patient's real-time condition.

To make the most of RPM data, it is crucial to have access to intuitive and user-friendly management platforms that effectively organize and present this information. Employing algorithms, ranging from simple to complex, can analyze and package RPM data in ways that can assist both clinicians and researchers in their decision-making processes. Moving forward, further design and validation of use cases of these technologies will be essential as remote patient monitoring expands.

 Adam Singer, MD, PhD, is a medical oncologist, genitourinary cancer specialist, and health technology researcher. He holds an MD from UCLA and a PhD in policy analysis from the Pardee RAND Graduate School.

Neutropenia. Cancer.net. September 2019. Accessed November 1, 2023. 

https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/managing-physical-side-effects/neutropenia

Lyman GH, Michels SL, Reynolds MW, et al. Risk of mortality in patients with cancer who experience febrile neutropenia. 

. 2010;116(23):5555-5563. doi:10.1002/cncr.25332

Griffiths EA, Roy V, Alwan L, et al. NCCN guidelines insights: hematopoietic growth factors, version 1.2022. 

. 2022;20(5):436-442. doi:10.6004/jnccn.2022.0026

Tai E, Guy GP, Dunbar A, et al. Cost of cancer-related neutropenia or fever hospitalizations, United States, 2012. 

. 2017;13(6):e552-e561. doi:10.1200/JOP.2016.019588

Articles

Neutropenic fever, a commonly occurring and potentially serious chemotherapy complication, requires careful monitoring and close observation.

Adam E. Singer, MD, PhD

Articles

Dr Singer on Toxicities Associated With First-Line IO/TKI Regimens in RCC

Dr Singer on the Efficacy of IO/TKI Doublets in Advanced RCC

Dr Singer on the Lack of Clinical Benefit for Immunotherapy Rechallenge in Advanced RCC

Transforming Neutropenic Fever Assessment with Remote Monitoring Technology