Nivolumab or Pembrolizumab Combos in Advanced Kidney Cancer?

Treating patients with advanced renal cell carcinoma (RCC) with combinations that include nivolumab (Opdivo) could result in lower costs related to adverse events in comparison with regimens that are based on pembrolizumab (Keytruda).

The use of nivolumab plusipilimumab (Yervoy) and nivolumab plus cabozantinib (Cabometyx) led to reductions of 22% to 86% in costs of all-cause and treatment-related grade 3/4 adverse events in comparison with pembrolizumab-based combinations.

The main contributors to costs of treatment-related adverse events varied by treatment regimen. Hypertension, increased levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as diarrhea drove the increase in costs with pembrolizumab-based combinations.

The finding comes from an analysis of patient data from clinical trials and could influence decisions as to which immunotherapy to use in the first line, say the authors.

The results suggest that nivolumab-based combinations “have a more favorable cost-benefit profile,” said lead author Bradley McGregor, MD, the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Nivolumab-based combinations may therefore “offer clinicians and payers a therapeutic option for previously untreated advanced RCC that may reduce the substantial clinical and economic impacts in this population.”

The article was published in The Oncologist on September 19. The study was supported by Bristol-Myers Squibb, manufacturer of nivolumab.

Immunotherapy Improves Survival

RCC is the most common type of kidney cancer. Over 76,000 new cases were diagnosed in 2021. It accounts for almost 14,000 deaths in the US, and 25% to 35% of patients have advanced or metastatic disease.

Until a few years ago, the 5-year survival rate for these patients was below 15%, but the introduction of novel therapeutic options such as immunotherapy-based combinations has offered better disease control and survival outcomes, the authors say.

The first of these combinations to be approved by the US Food and Drug Administration (FDA) for the first-line treatment of intermediate/poor-risk advanced RCC was nivolumab plus ipilimumab, in April 2018. The approval was based on the CheckMate 214 trial.

This approval was followed in April 2019 by approval of pembrolizumab plus axitinib (Inlyta) for the first-line treatment of advanced RCC. That approval was based on results from KEYNOTE-426, which showed improved outcomes in comparison with standard of care.

CheckMate 9ER, in which nivolumab plus cabozantinib doubled progression-free survival and significantly improved overall survival, led to the FDA approval of the combination in January 2021 for treatment-naive patients with advanced RCC in any risk group.

In August 2021, pembrolizumab plus lenvatinib (Lenvima) was approved for the same indication following the results of KEYNOTE-581.

Although immunotherapy improves survival, it comes with an increase in toxicity.

The researchers note that rates of all-cause grade ≥3 adverse events with the immunotherapy combinations were higher than those seen with a comparator, which in all of the trials was sunitinib (Sutent).

Moreover, “there is currently a paucity of evidence on the economic benefits and risks associated with these therapies.” Given the financial toxicity suffered by cancer patients in the US, such information could be valuable for healthcare decisionmakers and payers.

Hence, the investigators set out to perform a descriptive analysis of the costs of all-cause and treatment-related grade 3/4 adverse events of the four immunotherapy combinations by evaluating individual patient-level data from the clinical trials.

They also examined the US 2017 Healthcare Cost and Utilization Project National Inpatient Database to determine the unit costs, including hospitalizations, for grade 3/4 adverse events, with costs adjusted to 2020 US dollars.

The researchers initially compared three combinations: nivolumab plus ipilimumab vs nivolumab plus cabozantinib vs pembrolizumab plus axitinib. The median follow-up was approximately 12.8 months.

They found that pembrolizumab plus axitinib incurred the highest costs for all-cause grade 3/4 adverse events, at US $5772 per patient. Costs for nivolumab plus cabozantinib were 22% lower, at $4508 per patient, and the costs for nivolumab plus ipilimumab were 53% lower, at $2703 per patient.

For treatment-related grade 3/4 adverse events, pembrolizumab plus axitinib again incurred the highest costs, at $4440 per patient. Costs for nivolumab plus cabozantinib were 39% lower, at $2722 per patient, and the costs for nivolumab plus ipilimumab were 83% lower, at $742 per patient.

Hypertension, increased ALT and AST, diarrhea, and palmar-plantar erythrodysesthesia syndrome accounted for 90% of the total costs for treatment-related adverse events associated with pembrolizumab plus axitinib and for 86% of the costs linked to nivolumab plus cabozantinib.

For nivolumab plus ipilimumab, all of the total costs for treatment-related adverse events were due to fatigue, diarrhea, rash, and pruritus.

The researchers compared costs for the same two nivolumab combinations with pembrolizumab plus lenvatinib, at a median follow-up of around 26.6 months.

Pembrolizumab plus lenvatinib incurred the highest costs for all-cause grade 3/4 adverse events, at $9285 per patient. Costs were 38% lower with nivolumab plus cabozantinib, at $5800 USD per patient, and were 66% lower with nivolumab plus ipilimumab, at $3120 per patient.

Regarding costs of treatment-related grade 3/4 adverse events, the team found a similar picture. Costs with pembrolizumab plus lenvatinib were $5030 per patient, vs $3162 with nivolumab plus cabozantinib (37% lower) and $863 per patient with nivolumab plus ipilimumab (83% lower).

The team notes that 58% of the total costs for treatment-related adverse events with pembrolizumab plus lenvatinib were due to hypertension, fatigue, weight loss, diarrhea, and hepatotoxicity, while hypertension, hepatotoxicity, fatigue, diarrhea, and stomatitis accounted for 69% of the costs with nivolumab plus cabozantinib.

For nivolumab plus ipilimumab, fatigue, hepatotoxicity, diarrhea, musculoskeletal disorders, and rash underlay 83% of the total costs for treatment-related adverse events.

Severe adverse events can lead to treatment discontinuation, additional health resource utilization, poorer clinical outcomes, and worse quality of life, the team points out.

“The different patterns of toxicities related to the use of immunotherapy-based combinations and the resulting clinical and economic impact for the patients, healthcare providers, and payers must be considered when selecting the appropriate treatment strategy,” they suggest.

The study was funded by Bristol-Myers Squibb. McGregor has relationships with Exelixis, Bristol-Myers Squibb, Pfizer, Seattle Genetics, Calithera, EMD Serono, Eisai, Asetellas, Dendreon, Nektar, Bayer (C/A), Exelixis, Pfizer, Seattle Genetics, and Calithera (RF). Other authors have disclosed numerous relevant financial relationships.

Oncologist. Published online September 19, 2022. Full text

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