Home > Proceedings in Oncology > Proceedings of the 2024 IKCS: Europe Symposium > Real-world experience of adjuvant pembrolizumab in resected renal cancer

Real-world experience of adjuvant pembrolizumab in resected renal cancer

Author(s)
Lijo James (email)×Lijo James (email)

Affiliation
Beatson West Of Scotland Cancer Centre Oncology Glasgow United Kingdom
Manreet Randhawa ×Manreet Randhawa

Affiliation
Beatson West Of Scotland Cancer Centre Oncology Glasgow United Kingdom
Balaji Venugopal ×Balaji Venugopal

Affiliation
Beatson West of Scotland Cancer Centre Oncology Glasgow United Kingdom
Sarah Slater ×Sarah Slater

Affiliation
Beatson West of Scotland Cancer Centre Oncology Glasgow United Kingdom
Caroline Forde ×Caroline Forde

Affiliation
Northern Ireland Cancer Centre,Belfast City Hospital Oncology Belfast United Kingdom
Gemma Clements ×Gemma Clements

Affiliation
Northern Ireland Cancer Centre,Belfast City Hospital Oncology Belfast United Kingdom
Karen Thompson ×Karen Thompson

Affiliation
Northern Ireland Cancer Centre,Belfast City Hospital Oncology Belfast United Kingdom
Alison Clayton ×Alison Clayton

Affiliation
Northern Ireland Cancer Centre,Belfast City Hospital Oncology Belfast United Kingdom

Conference
IKCS-EU 2024
Abstract
Background: Pembrolizumab is the only adjuvant treatment demonstrating improvements in disease-free and overall survival in patients post-nephrectomy for clear cell renal cell carcinoma. We assess the real-world experience in the Beatson West of Scotland Cancer Centre and Northern Ireland Cancer Centre, since its approval in October 2022 by SMC and NICE.

Methods: Electronic medical records of eligible patients were reviewed between October 2022 and December 2023. Data on patient demographics, pathology, multidisciplinary team meeting (MDT) discussion, rates and reasons for declining treatment and toxicity was collected.

Results: 166 patients were identified at MDT as being eligible for adjuvant pembrolizumab based on pathology as per Keynote-564 inclusion criteria. 92.6% were intermediate-high risk with 7.9% having sarcomatoid features. 149 patients (89.8%) were reviewed in the oncology clinic, with 17 not referred, mainly due to co-morbidities felt to preclude adjuvant immunotherapy.
80 patients (48.1%) proceeded to adjuvant treatment (69 on pembrolizumab and 11 on a clinical trial). Reasons for the 67 pts not proceeding, included patient choice (n=27), co-morbidities (n=29) and metastatic disease on postoperative imaging (n=13). Immune-related adverse events (irAE) of any grade have occurred in 59 patients (85.5%) with grade 3 or 4 events occurring in 5 (7.2%). Steroids have been required in 13 patients (18.8%) and 6 (8.6%) have required hospitalisation for irAE. Treatment discontinuation due to adverse events has occurred in 13 patients (18.8%). 51 patients continue on pembrolizumab with 5 to date having completed the one-year course.

Conclusion: Our real-world experience demonstrates the majority of patients eligible for adjuvant pembrolizumab based on pathology are reviewed by an oncologist for discussion. Approximately half of patients proceed with adjuvant treatment. The adverse event profile, steroid use and discontinuation rates are comparable to date with the Keynote-564 data.

Keywords
Adjuvant treatment, Pembrolizumab, Real-world experience, Resected renal cancer, , , ,

Doi
https://doi.org/10.55788/598f683c

INTRODUCTION


Pembrolizumab is an immune checkpoint inhibitor used to treat various malignancies. It is a selective monoclonal antibody that inhibits programmed cell death (PD-1) and activates the T cell response. In the setting of renal cancer, pembrolizumab was first used in combination with axitinib as the standard first-line treatment for metastatic or advanced renal cancer.

The KeyNote 426 trial showed significant improvements in progression-free and overall survival.2 More recently, the Keynote 564 trial has demonstrated its use in the adjuvant setting. This landmark phase 3 trial randomised patients to pembrolizumab 200 mg 3 weekly intravenously or placebo and showed that adjuvant pembrolizumab improved disease-free and overall survival in patients with renal cancer.1,7

Pembrolizumab is the only adjuvant immune checkpoint inhibitor recommended for post-nephrectomy patients who fit the inclusion criteria. The inclusion criteria for the Keynote 564 trial were age 18 years or above, histologically confirmed clear cell locoregional renal cell cancer, nephrectomy, and high risk of recurrence. A high risk of recurrence is defined as a stage 2 tumour with nuclear grade 4 or sarcomatoid differentiation or stage 3 tumour or higher, regional lymph node metastasis, or stage M1 with NED, whereas M1 NED (No Evidence of Disease on postoperative scans) is defined as resection of primary tumour and solid, isolated, and soft tissue metastasis.1,7

We assessed the real-world experience at the Beatson West of Scotland and Northern Ireland Cancer Centre, since approval in October 2022 by both the Scottish Medicines Consortium and the National Institute for Health and Care Excellence. The main study objective was to assess our experience with adjuvant pembrolizumab in resected renal cancer as there is a paucity of real-world evidence of adjuvant pembrolizumab given the recent approval.

METHODS


The electronic medical records of eligible patients were reviewed between October 2022 and December 2023. All patients were discussed at the multidisciplinary team (MDT) meeting and those deemed eligible based on histopathological results according to the inclusion criteria of the KeyNote 564 trial were included. Data on demographic characteristics, pathology, reasons for not proceeding to treatment and toxicity were collected. Patients in adjuvant trials were excluded from the review. Since this is a retrospective audit, informed consent was not obtained and does not require an IRB review of the protocol.

RESULTS


The data cutoff was December 19, 2023, for the final analysis and the median follow-up was 5.5 months. A total of 166 patients were identified as eligible for adjuvant pembrolizumab. Of these, 151 had intermediate-to-high-risk disease (92.6%), (5.4%) had high-risk disease, and 1.8% had M1NED. Sarcomatoid features were present in 7.9% of the cohort. 44% of patients with high-risk disease proceeded to adjuvant treatment or clinical trials, whereas 49% of intermediate-high-risk patients proceeded to adjuvant treatment including clinical trials.149 patients (89.8%) were reviewed in the oncology clinic, with 17 patients not being referred from the MDT, mainly due to comorbidities felt to preclude adjuvant immunotherapy by the clinicians present in the MDT. 80/166 patients (48.1%) proceeded to adjuvant treatment (69 on pembrolizumab and 11 on a clinical trial). 69 patients who were reviewed and did not proceed with adjuvant pembrolizumab, reasons included patient choice (n=27), comorbidities (n=29), and metastatic disease on postoperative imaging (n=13) (Figure).

Figure. Consort Diagram1,7



The median age of patients proceeding to adjuvant pembrolizumab (n=69) was 61 years, and the male-to-female ratio was 2:1 (46 male and 23 female patients). In the patients who proceeded to adjuvant pembrolizumab, 63 (91.3%) had intermediate-high-risk disease, 4 (5.7%) had high-risk disease, and 2 (2.8%) had M1NED (Table 1).

Table 1. Patient Characteristics 1,7
Patient CharacteristicsPatients who proceeded to adjuvant pembrolizumab treatment (n=69)Patients who did not receive any or pembrolizumab adjuvant treatment including clinical trials (n=86)
Median age, years6168
≥65, n (%)27 (39.1)54 (62.7)
Male sex, n (%)46 (66.6)52 (60.4)
Female sex, n (%)23 (33.3)34 (39.5)
Sarcomatoid features, n (%)8 (11.6)3 (3.4)
Disease risk category, n (%)
M0, intermediate-to-high risk
M0, high risk
M1 NED
63 (91.3)

4 (5.7)
2 (2.8)
80 (93)

5 (5.8)
1 (1.1)
T stage, n (%)
pT2
pT3
pT4
none
67 (97.1)
2 (2.8)
2 (2.3)
84 (97.6)
none

Eight (11.5%) patients had sacramatoid features in the tumour pathology. Immune-related adverse events (irAEs) of any grade occurred in 59 patients (85.5%) with grade 3 or 4 events occurring in 5 (7.2%) (Table 2). High-dose steroids were required in 13 patients (18.8%), and 6 (8.6%) patients required hospitalisation for immune-related adverse events. Treatment discontinuation due to adverse events occurred in 13 patients (18.8%). 51 patients continue on pembrolizumab, with five to date having completed 12 months of treatment. None of the patients had disease progression while on treatment or shortly after discontinuation.

Table 2. Adverse events in patients treated with adjuvant pembrolizumab1,7
Immune related AEs, n (%)
Any grade
Grade 3 or 4
59 (85.5%)
5 (7.2%)
Common irAEs (Any grade), n (%)
Fatigue
Thyroid dysfunction
Pruritus
Rash
Arthralgia
Diarrhoea
Nephritis
Increase in blood creatinine level
Colitis
Hepatitis
Constipation
Pneumonitis
Myocarditis
Polymyalgia rheumatica
30 (43.4%)
19 (27.5%)
13 (18.8%)
12 (17.4%)
12 (17.4%)
12 (17.4%)
3 (4.3%)
3 (4.3%)
2 (2.9%)
2 (2.9%)
2 (2.9%)
1 (1.4%)
1 (1.4%)
1 (1.4%)
AE, adverse event; irAE, immune-related adverse event

DISCUSSION


The Keynote 426 trial showed that patients with resected renal cancer benefit from adjuvant pembrolizumab. There are a few other trials in this setting, including CheckMate 914, IMmotion010, and PROSPER does not show any survival benefits and none of these trials met its primary endpoint. Checkmate 914 assessed the role of a combination of ipilimumab and nivolumab in an adjuvant setting in patients with localised renal cell carcinoma and it did not reach its primary endpoint of disease-free survival.5 In the IMmotion010 trial, adjuvant atezolizumab also showed no improvement in disease-free survival when compared with placebo whereas in the PROSPER trial which compared the outcomes of nephrectomy versus giving a single dose of nivolumab before surgery and nine doses after surgery with observation. This trial also showed no disease-free survival benefit at interim analysis.4,6

In the KeyNote 564 trial, a total of 496 patients were randomly assigned to receive adjuvant pembrolizumab and 498 patients to receive placebo. Pembrolizumab was administered at a dose of 200mg every 3 weeks for up to 17 cycles (approximately 1 year).1,7 In our real-world data only 69 patients received adjuvant pembrolizumab and this was given at a dose of 400mg every 6 weeks for a total of 9 cycles.

The reason we adopted 6 weekly dosing is that studies have shown similar safety and efficacy as three weekly dosing.3 It is easier for patients to have 9 cycles versus 17 in terms of travel and parking at oncology departments, clinic visits, and local blood tests. In terms of dealing with a lack of capacity and staffing issues within most UK oncology departments, 6 weekly infusions are hugely advantageous and have made the clinical workload of absorbing adjuvant pembrolizumab manageable.

In our study, only half of the patients discussed at MDT proceeded to adjuvant pembrolizumab and therefore, as numbers are likely to increase in future as patient groups become more aware and accepting of adjuvant pembrolizumab, oncology teams will need to adapt to this increased workload. For example, they may need to consider separating adjuvant and metastatic patients such as adjuvant NMP (non-medical prescribing) clinics.

There is a 12-week window from nephrectomy to starting adjuvant pembrolizumab. During this time patient cases need MDT discussion of pathology and post-surgery CT. Due to the delays in getting CT scans, some patients met the oncologists to discuss adjuvant pembrolizumab prior to getting their CT results. Our data show that 18.8 % of patients had already progressed on CT scans prior to starting adjuvant pembrolizumab. We know this is an incredibly stressful time for patients and is made worse by discussing the likelihood of adjuvant pembrolizumab and then being told they will be starting palliative SACT (systemic anti-cancer treatment) instead. Therefore, it is essential that the adjuvant pathway is streamlined from MDT meetings so that the post-operative CT scan is done before the first oncology appointment. However, we recognise that radiology departments are under huge pressure and this is not always possible. Furthermore, with the advent of clinical trials looking at mRNA vaccines for adjuvant renal patients the strict timelines will become even more crucial and therefore, maximum effort will need to be made to streamline the MDT meeting process and adjuvant service. Therefore, an adjuvant lead oncologist may need to be considered in future.

In our cohort, patients were selected for adjuvant pembrolizumab according to KeyNote 564 inclusion criteria and the patient demographics including median age and M:F (male to female ratio) were comparable. In the phase 3 trial, 86.1% of patients had M0, an intermediate-to-high-risk pathology compared to 92.6% in our cohort. There were fewer patients with high-risk disease or in the M1NED group compared to the trial population. A total of 1,406 patients were screened for the phase 3 trial with 412 patients being excluded. The most common reason was the presence of baseline disease at the time of screening (37.9%).1,7 From our data the most common reason for not proceeding with adjuvant treatment was patient choice and the main reason behind this was concerns about toxicities of treatment. The next common reason for exclusion from treatment was comorbidities. The most common comorbidity that precluded treatment was poor renal function.

As adjuvant treatment is a new concept in renal cancer, oncologists would not have previously met patients with renal cancer at this stage in their treatment and it would be their surgeons explaining their risk of recurrence. Anecdotally, it was noted that some patients meeting the oncologists to discuss adjuvant pembrolizumab were not aware of their percentage of risk of recurrence after nephrectomy and they were expecting a lower risk of recurrence. In future studies, we are interested in investigating patients' understanding of the high and intermediate risk of renal cancer, how surgical teams discuss this with patients and whether the risk of recurrence is one of the main determining factors in accepting adjuvant systemic anti-cancer treatment. Furthermore, whether the arrival of adjuvant immunotherapy has changed the discussions between surgeons and patients about the risk of renal cancer recurrence.

In the Keynote 564 trial, the most common toxicity was fatigue (29.75) followed by diarrhoea (25.4%).1,7 Our data also showed fatigue as the common side effect which was reported by 43.4% of patients, followed by thyroid dysfunction (27.5%). Twelve (17.3%) patients were started on levothyroxine. Pruritis (18.8%) and rash (17.4%) were also common toxicity in our cohort, which is comparable to trial data where 22.7% and 20.1% respectively.1,7 Treatment-related adverse events of any grade in patients who received adjuvant pembrolizumab as assessed by the investigator in the trial was 79.1% and Grade 3 to 5 was 18.9%.1,7 Our data showed that 85.5% of patients had experienced toxicities of any grade and grade 3 or 4 toxicities occurred in 7.2% of patients. Discontinuation of pembrolizumab due to adverse events occurred in 7.6% of patients in the trial whereas 18.8% in our patients.

Our data showed that a majority of patients are continuing on treatment and only five patients had completed a year of adjuvant treatment. The median follow-up was also only 5.5 months which was short and a longer duration of median follow-up is needed for accurate comparison. We know that immunotherapy side effects can occur late in treatment so we accept that our toxicity data is premature and will continue to collect this data. We will also collect data on not only steroid usage and type of toxicity but also medical speciality referrals, as we continue to learn that immunotherapy can result in multi-system toxicities that often involve medical expertise. Furthermore, toxicities can be lifelong for example endocrine abnormalities, which is an essential consideration when consenting adjuvant patients for immunotherapy.

Nearly a fifth of our cohort of patients did not complete their 9 cycles of pembrolizumab and therefore, we will have to consider guidelines for when we refer these patients back for surgical surveillance. While patients are on pembrolizumab under oncology surveillance the frequency of CT scans tends to be every 3-4 months whereas, surgical surveillance is routinely every 6 months. For patients completing 9 cycles, they are referred back to the surgical follow-up within 6 weeks of the last infusion. It is recognised that patients with significant immunotherapy toxicity may require more clinical reviews than surgical surveillance and are likely to stay under oncology review for longer. Most large cancer centres are developing immunotherapy toxicity clinics and MDT team meetings, and all centres will likely need to consider developing these.

CONCLUSION


Our real-world experience demonstrates that the majority of patients eligible for adjuvant pembrolizumab based on pathology are reviewed by an oncologist for discussion. Approximately 50% of patients proceed with adjuvant treatment. The early adverse event profile, steroid use, and discontinuation rates are comparable to date with the Keynote-564 data. The majority of patients are still undergoing treatment, and the data is premature so further follow-up is required. The advent of adjuvant treatment for renal cancer is an exciting time to learn invaluable lessons about streamlining MDT decision-making and treatment pathways especially when considering mRNA vaccine trials are now underway. While our real-world experience of adjuvant pembrolizumab mirrors the KEYNOTE-564 trial, there are constraints in this study including a limited sample size, a shorter follow-up period, and a small number of patients finishing the treatment. Further follow-up is necessary.

Conflict of interest


Manreet Randhawa has received speaker fees from MSD; Balaji Venugopal has received speaker fees from MSD; Caroline Ford has received speaker fees from MSD.

FUNDING


No funding was received for this work.

REFERENCES


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©2024 the author(s). Published with license by Medicom Medical Publishers.
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