3.3 Treatment criteria for initiation of checkpoint inhibitors

3.3 Treatment criteria for initiation of checkpoint inhibitors¹

(Ipilimumab/Nivolumab as 1st line or Nivolumab, as 2nd or 3rd line treatment).

For most patients, checkpoint inhibitors (CPIs) are palliative treatment with the purpose of symptom relief and life extension. However, individual patients achieve a complete response for a shorter or longer period of time.

Checkpoint inhibitors are given intravenously either every 3 weeks (combination immunotherapy) – a total of 4 cycles – after which Nivolumab is continued alone, or every 4 weeks (monotherapy) i.e. a cycle extends over either 3 or 4 weeks. The patient will be evaluated by CT of the chest and abdomen (and MRI scan of the cerebrum for cerebral metastases) every 3 months.

For 1st line combination immunotherapy:

The median progression-free survival (mPFS) in patients belonging to intermediate or poor prognostic group is 11.6 months. The median overall survival (mOS) is not yet known (data not yet mature)
According to the RECIST criteria, 72.7% of the patients have an effect of treatment with either:

1. Complete response (CR) – 10.1%
2. Partial response (PR) – 32%
3. Stable disease (SD) – 30.6%

For 2nd-3rd line Nivolumab (monotherapy):

mPFS is 4.6 months and mOS is 25 months
According to the RECIST criteria, 59% of the patients have either:
1. Complete response (CR) – 1%
2. Partial response (PR) – 24%
3. Stable disease (SD) – 34%

First visit to the Oncology Department

At the first visit to the Oncology Department, a full medical record must be recorded, focusing on:

Medical history:

Dispositions (family history of cancer with particular emphasis on cases of kidney cancer)
Symptoms (fatigue, weight loss, impaired appetite, sweating/hot flushes, pain, etc.)
Comorbidity (hypertension, ischaemic heart disease, impaired cardiac pump function (EF) and its cause, arrhythmias, cerebral apoplexy, diabetes mellitus, renal insufficiency, autoimmune and other chronic disorders)
Full medication status. It should state whether the patient is undergoing:

1. Immunosuppressive treatment, what and why

Social information

1. Civil status
2. Network
3. Employment (working, sick leave, early retirement, pensioner or other)
4. Functional level (self-reliant, need help with self-care or other)

Clinical assessment:

General condition (good, acute or chronic condition) incl. performance status (PS)
Vital signs incl. BP, pulse, temperature, saturation and weight
Objective examination incl. evaluation of enlarged lymph nodes, stethoscopy of heart and lungs, examination of abdomen, extremities and skin

Paraclinical:

At the first outpatient visit, the following must be examined:

Blood tests: haematology (Hb, platelets, leukocytes + differential count), fluid counts (creatinine, urea, sodium, potassium, ionised calcium and magnesium), liver function tests (ALT, AST, LDH, alkaline phosphatase, INR and coagulation counts (2.7 + 10), CRP, TSH, cortisol, testosterone (male), amylase, CK-MB and troponin
For combination immunotherapy: CK-MB and troponin
ECG: rhythm, acute changes and QTc interval assessment
MRI scan: cerebrum (performed or ordered)
CT scan: thorax and abdomen (baseline must be <1 month old)
MUGA: assessment of the heart’s pumping function (performed or ordered)
IMDC: risk stratification

Treatment criteria

The following criteria must be met in connection with initiation of checkpoint inhibitor. Deviations must be discussed with a specialist, and this must be documented in the medical record.
*If no (explain in medical record)

TREATMENT CRITERIA	YES	NO*	ACTIONS IF ANSWER IS NO
Bioptic verified mRCC – clear cell histology of intermediate or poor prognosis group if combination immunotherapy
Performance status (PS): Monotherapy < 2 Combination therapy < 1
Renal function eGFR > 30 ml/min			Checkpoint inhibitors are not renally excreted. Can therefore be offered to patients with poor renal function, but it must be discussed with a specialist
Liver function Bilirubin < 1.5 x upper limit of normal AST/ALT < 3 x upper limit of normal or < 5 when liver metastases
ECG QTcF <450 ms for men and <470 ms for women			Review the patient’s medication list for medications that may cause prolonged QTc. Consult with a cardiologist
Blood pressure < 140/90 mmHg			Consider white-coat hypertention and ask the patient to take blood pressure at home or at their GP. If continued high blood pressure, initiate anti-hypertensive medications or intensify anti-hypertensives already used via GP (see section 5.2.2)
Ejection fraction (EF) > 40% (measured by MUGA)			Refer the patient for cardiological assessment for ECHO and initiation of anticongestive therapy if EF < 40% is confirmed. The above requirements are particularly important in combination immunotherapy
No autoimmune diseases			Exceptions: • Well-regulated type 1 diabetes • Hypothyroidism following autoimmune thyroiditis requiring substitution therapy only • Vitiligo In the event of other autoimmune diseases, consult a specialist
No prednisolone treatment > 10 mg or other immunosuppressive therapy			Inhalation steroid or treatment of adrenal cortex insufficiency (hydrocortisone) are permitted
Not known to have HIV or hepatitis B or C
MRI scan of the cerebrum without cerebral metastases			In cerebral metastases: 1) If the patient is asymptomatic and has 1–3 cerebral metastases, refer to SRK conference for radiation therapy. CPI can be initiated 2) If the patient is symptomatic and has 1–3 cerebral metastases, begin steroid treatment in accordance with guidelines and refer to SRK conference. CPI cannot be started before discontinuing prednisolone 3) If the patient has multiple cerebral metastases but asymptomatic. Initiate CPI 4) If the patient has multiple metastases and has symptoms, begin steroid treatment. Initiate TKI treatment and consider whole-brain radiation
CT scan of chest and abdomen < 1 month			If baseline CT scan > 1 month, consider ordering a subacute CT scan as new baseline

Links to summaries of product characteristics:

Instructions for patient/relative

Review of the immune-related adverse reactions and CTC form and emphasise the importance of contacting the department in the event of symptoms
Dispense supportive medication (Domperidone and Imolope)

Assessment during treatment

The patient is assessed at the outpatient clinic by a doctor or nurse every 3 or 4 weeks, where:

Clinical assessment and checking of BP, pulse, weight, temperature and saturation, if applicable
Toxicity registration according to CTCAE version 5.0 (see section on grading)
Check of blood tests (haematology, fluid values incl. ionised calcium + magnesium, liver function tests, CRP, TSH, cortisol, testosterone (male), amylase + CK-MB and troponin during combination immunotherapy)
Medication status
Assessment of new symptoms
Decisions on postponement or other measures (see section on adverse reactions to checkpoint inhibitors)

Evaluation of response

The efficacy of checkpoint inhibitors is assessed every 3 months. (12 weeks) with CT scan of the chest and abdomen and MRI scan of the cerebrum if the patient is known to have cerebral metastases.

Assessment of response depends on: