Anti–PD-1/anti–CTLA-4 combination immunotherapy in a patient with poor-risk metastatic RCC
Presentation and investigations
A 59-year-old gentleman with good past health was admitted to hospital in November 2018 due to right lower quadrant pain. Physical examination revealed a right ballotable kidney mass. The patient was haemodynamically stable.
CT scan with contrast showed an extensive right kidney tumour with multiple metastases in the liver, peritoneum, bilateral lungs and right adrenal gland. There was also right renal vein invasion extending into the suprarenal level of the inferior vena cava. (Figure 1A) Renal biopsy confirmed clear-cell renal cell carcinoma (ccRCC).
The patient required a wheelchair on admission and was partially bedbound. He was deemed to have poor performance status (PS) with Eastern Cooperative Oncology Group (ECOG) PS of 2. His disease was classified as poor-risk based on the International Metastatic RCC Database Consortium (IMDC) prognostic risk model.
Treatment and response
In view of poor-risk disease, combination therapy with the programmed death 1 (PD-1) inhibitor nivolumab (3 mg/kg) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab (1 mg/kg) was started in December 2018. After completing four 3-weekly cycles of nivolumab/ipilimumab combination therapy, the patient has been receiving nivolumab (3 mg/kg) maintenance every 2 weeks since April 2019.
The patient demonstrated significant symptomatic improvement and regained the ability to walk following treatment. Treatment was well tolerated, with grade 1 fatigue and grade 1 pruritus being the only adverse effects, which were managed with rest and as-needed chlorpheniramine, respectively.
In August 2019, from the 12th cycle onwards, nivolumab was switched to a flat dose of 480 mg every 4 weeks. A CT scan in August 2019 confirmed partial response (PR), with a significant reduction in size of the kidney tumour as well as resolution of lung and peritoneal metastases. (Figure 1B)
Follow-up in September 2019 showed low morning cortisol level, while results of short Synacthen test indicated an inadequate adrenal response. The patient’s cortisol level soon normalized following hydrocortisone treatment.
The patient has continued nivolumab maintenance and has received a total of 24 cycles as of August 2020 (ie, over 20 months of treatment). He demonstrated sustained PR with no symptomatic deterioration and has remained ambulatory, with an ECOG PS of 0. Recent chest X-ray showed no obvious lung nodules.
First-line systemic treatment options for advanced/metastatic ccRCC include immunotherapies and tyrosine kinase inhibitors (TKIs), the choice of which depends on factors such as the patient’s PS, prognostic risk stratification and comorbidities, and the treatments’ adverse event (AE) profile.1
The US National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend nivolumab/ipilimumab combination therapy as a first-line treatment option for intermediate-/poor-risk patients, such as our patient.2-4 Nivolumab plus ipilimumab could also be considered in patients with major contraindications to TKIs, such as a history of uncontrolled hypertension or thromboembolism events requiring anticoagulant treatment.1
The cellular and molecular mechanism of combination immunotherapy may be distinct from those that mediated by monotherapy. Simulateous blockade of both CTLA-4 and PD-1 may lead to functional convergence through enhancement of T-cell activition. In addition, engagement of distinct cell populations by anti–CTLA-4 and anti–PD-1 may also contribute to the enhanced efficacy of compination therapy, with anti–CTLA-4 but not anti–PD-1 leading to the expansion of tumour-infiltrating CD4 cell population whereas anti–PD-1 primarily acts through targeting CD8 T-cell population.6
The first-line use of nivolumab plus ipilimumab in advanced RCC is supported by evidence from the CheckMate 214 trial, which randomized (1:1) 1,096 patients with previously untreated advanced RCC to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or once-daily sunitinib (50 mg) for 4 weeks (6-week cycle). 7 At 42-month follow-up, nivolumab plus ipilimumab demonstrated a significant improvement in overall survival (OS) vs sunitinib monotherapy (median, 47.0 months vs 26.6 months; rate, 52 percent vs 39 percent; hazard ratio [HR], 0.66; 95 percent confidence interval [CI], 0.55 to 0.80; p<0.0001).7
An extended 4-year follow-up of the trial demonstrated continuous benefits with nivolumab plus ipilimumab vs sunitinib monotherapy in OS (median, 48.1 months vs 26.6 months; HR, 0.65; 95 percent Cl, 0.54 to 0.78) and progression-free survival (PFS) (median, 11.2 months vs 8.3 months; HR, 0.74; 95 percent CI, 0.62 to 0.88) among 847 intermediate-/poor-risk patients.8 In these intermediate-/poor-risk patients, a significant improvement in objective response rate (ORR; 42 percent vs 27 percent; p<0.0001) and higher complete response (CR, 10 percent vs 1 percent) rate as assessed by independent radiology review were also achieved with nivolumab plus ipilimumab vs sunitinib.8
Of note, the OS benefit with nivolumab plus ipilimumab vs sunitinib in intermediate-/poor-risk patients was evident regardless of programmed death-ligand 1 (PD-L1) status (PD-L1 <1 percent: HR, 0.73; 95 percent CI, 0.56 to 0.96) (PD-L1 ≥1 percent: HR, 0.45; 95 percent CI, 0.29 to 0.71).9
Overall, safety outcomes in the 4-year follow-up of CheckMate 214 were consistent with previous reports.8
In the 42-month follow-up of CheckMate 214, the incidence of grade 3/4 select TRAEs was the highest within the first 6 months of treatment (22 percent), and decreased substantially thereafter (4 percent at 6–≤12 months, 2 percent at 12–≤18 months).7
Regular monitoring of adrenocorticotropic hormone (ACTH) and cortisol level, as well as thyroid function and glucose level, is recommended during immuno-oncology treatment, including nivolumab and ipilimumab, for early detection and management of potential endocrine immune-related AEs (IRAEs).10 Patients should be educated about signs and symptoms of potential IRAEs that should be reported to clinicians.
This case illustrates the efficacy in terms of long-term survival, as well as safety of nivolumab plus ipilimumab as first-line treatment in a poor-risk patient with metastatic ccRCC. The patient demonstrated significant improvements in symptoms and function following nivolumab plus ipilimumab combination treatment, which was well tolerated. As of August 2020, 24 cycles of nivolumab had been given. TRAEs of skin rash and low cortisol level, which developed in the first few months of treatment, were well managed with as-needed chlorpheniramine and steroid replacement along with regular monitoring of endocrine function, respectively.