Nivolumab in Combination With Ipilimumab in Patients With Metastatic Renal Cell Carcinoma
Indikation (Clinical Trials):
Carcinoma, Carcinoma, Renal Cell
Swiss Group for Clinical Cancer Research
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Despite the encouraging results of recent trials, only a minority of patients shows
significant response to single agent immunotherapy with nivolumab (Overall response rate
(ORR) around 20%). Therefore, further investigations are urgently needed to improve the
prognosis of patients with mRCC. Recent analyses of phase I trials in mRCC and also in
non-small-cell lung carcinoma (NSCLC) patients as well as more advanced studies in melanoma
patients have provided evidence that combination of immunotherapies can improve response
rates and response duration.
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather
than as self and can be effectively attacked by an activated immune system. An effective
immune response in this setting is thought to rely on immune surveillance of tumor antigens
expressed on cancer cells that ultimately results in an adaptive immune response and cancer
cell death. Meanwhile, tumor progression may depend upon acquisition of traits that allow
cancer cells to evade immunosurveillance and escape effective innate and adaptive immune
responses. Current immunotherapy efforts attempt to break the apparent tolerance of the
immune system to tumor cells and antigens by either introducing cancer antigens by
therapeutic vaccination or by modulating regulatory checkpoints of the immune system.
Dysfunctional T cells in cancer show an upregulation of inhibitory receptors (T cell
exhaustion). Combined blockade of inhibitory receptors including CTLA-4 and PD-1 are
considered to act synergistically. Indeed, early trials in mRCC showed improved response
rates and combinations have also demonstrated to be prolonging progression-free survival in
melanoma. While CTLA-4 is mainly involved in transmitting negative signals in T cells during
priming in the lymph node, PD-1 is thought to mainly inhibit T cell cytotoxicity within the
tumor by engagement of ligands PD-L1 and PD-L2, which are upregulated by tumor cells and
inflammatory cells within the tumor microenvironment as shield against the immune attack. It
is therefore reasonable to combine PD-1 blockade with CTLA-4 blockade and this has been
tested with an intriguing doubling of ORR in a phase I trial in patients with mRCC. An
important aspect of any combination therapy is the question of additional/ excessive
toxicity. In that trial the combination of nivolumab 3mg/kg/q3w (cont.) and ipilimumab
1mg/kg/q3w (4 times) proved to be safe, efficacious and feasible (much better safety profile
in patients with mRCC compared to patients in melanoma trials). 78% of patients had any AE,
but only 28% a grade 3-4 AE event. While diarrhea was quite common, only 4.8% had grade 3-4
diarrhea. Other treatment related immune-mediated AEs, especially endocrinopathy,
pneumonitis, skin disorders were recorded at lower grades than 3. No deaths were reported for
this combination. The overall response rate was 43% with durable responses of 78% in patients
that had an initial response (durable responses).
Moreover, recent variations of dosing schedules and strengths of the nivolumab-ipilimumab
combinations have shown improvement of toxicity rates with no loss of efficacy. For example,
ipilimumab every 6 weeks at 1mg/kg was shown to be well tolerated in patients with non-small
cell lung cancer when combined with nivolumab.
Nivolumab has proven efficacy and a favorable toxicity profile as a 2nd line therapy in mRCC.
It is therefore destined to become the standard therapy after a first line TKI therapy.
However, only a minority of patients shows clear responses leaving plenty of room for
improvement. The addition of a further agent including blockade of CTLA-4 that acts
synergistically could improve the response rate and also extend the progression-free and
overall survival in patients with mRCC.
The addition of ipilimumab to nivolumab in order to increase response rates and induce more
often durable remissions in patients is a reasonable next step and is currently tested in
several randomized trials. However, at this point it is unclear which subgroup benefits most
from the combination of CTLA-4 and PD-1 blockade and the optimal regimen/schedule remains
unknown. To this end, this trial will test a combination of ipilimumab with nivolumab at an
alternate schedule and a subsequent adaptation of the treatment regimen to the individual
response with the aim to increase efficacy while reducing toxicity in mRCC patients.
Ipilimumab is often used only in the first weeks of antineoplastic treatment for initial
immune priming, allowing the presumption that it could be stopped after an initial priming
phase. A phase I dose finding study is not needed, as experience with this dose and even
higher doses have been reported and data are on file at Bristol-Myers Squibb (BMS). In
addition, sequential biopsies and biomarker studies shall identify patients that benefit the
most of a combination immunotherapy. In this trial, it was decided to have a nivolumab
lead-in phase to be able to determine whether any acute side effect is nivolumab or
- Written informed consent according to Swiss law and ICH/GCP regulations before
registration and prior to any trial specific procedures
- Histologically or cytologically confirmed, locally advanced and/or metastatic clear
cell RCC not amenable to surgery or definitive radiotherapy, and requiring systemic
- Patient able and willing to provide serial biopsies and blood drawings (initial, at 14
weeks (except for patient in the expansion cohort), and at progression).
- Measurable disease
- In case of second line patients, the previous therapy must be stopped at least 2 weeks
prior to registration
- Age ≥ 18 years
- WHO performance status of 0-1
- Bone marrow function: neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L
- Hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's
disease ≤ 3.0 x ULN), AST, ALT and AP ≤ 2.5 x ULN (≤ 5 x ULN if significant hepatic
metastasis is suspected to be the cause for enzyme elevation)
- Renal function: eGFR > 20 mL/min/1.732
- Cardiac function: NYHA ≤ 2. In case of cardiac insufficiency NYHA 1 or 2, Left
ventricular Ejection Fraction (LVEF) ≥ 35% as determined by echocardiography (ECHO) or
multigated acquisition (MUGA) scan
- Women with child-bearing potential are using effective contraception are not pregnant
or lactating and agree not to become pregnant during trial treatment and during 5
months thereafter. A negative pregnancy test before inclusion into the trial is
required for all women with child-bearing potential.
- Men agree not to father a child during trial treatment and during 5 months thereafter
- Uncontrolled CNS metastases. Patients with asymptomatic CNS metastases (at least 2
weeks after radiotherapy or surgery and steroids with prednisone equivalent of 10 mg
or lower) are eligible
- History of hematologic or primary solid tumor malignancy, unless in remission for at
least 3 years from registration with the exception of pT1-2 prostate cancer Gleason
score < 6, adequately treated cervical carcinoma in situ, or localized non-melanoma
- More than one previous line of systemic therapy for mRCC
- Prior immunotherapy.
- Concurrent or recent (within 30 days of registration) treatment with any other
- Concomitant use of other anti-cancer drugs or radiotherapy except for local pain
control (radiotherapy of target lesion not allowed)
- Immunosuppressive medications (such as but not limited to: methotrexate, azathioprine,
and TNF-α blockers) within 30 days before registration
- systemic corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent
- immunosuppressive medications for patients with contrast allergies
- inhaled and intranasal corticosteroids
- Live attenuated vaccination within 30 days prior to registration and for 30 days after
last dose of any of the trial drugs. Inactivated viruses, such as those in the
influenza vaccine, are permitted
- History of or active auto-immune disease with the exception of diabetes mellitus type
- Human immunodeficiency virus (HIV) infection or active chronic Hepatitis C or
Hepatitis B Virus infection or any uncontrolled active systemic infection requiring
intravenous (iv) antimicrobial treatment
- Known hypersensitivity to trial drug(s) or to any component of the trial drug(s)
- Any other serious underlying medical, psychiatric, psychological, familial or
geographical condition, which in the judgment of the investigator may interfere with
the planned staging, treatment and follow-up, affect patient compliance or place the
patient at high risk from treatment-related complications.
1. Overall response rate (ORR) (Time Frame - at 2 years.):
ORR is defined as proportion of patients achieving partial response (PR) or complete response (CR) according to RECIST v1.1 at any time between registration and documented disease progression*, death, or subsequent therapy, whichever occurs first. *PD before the 3rd administration of ipilimumab not leading to treatment discontinuation does not count as progression for this endpoint. Furthermore, the additional tumor assessment at 20 weeks for patients with PD n.c.s. before week 20 will not be taken into consideration for calculation of this endpoint.
1. Progression-free survival (PFS) (Time Frame - at weeks 8, 14, 20, 26, and then every 12 weeks up to 2 years.):
PFS is defined as the time from registration until progression according to RECIST v1.1 or death from any cause, whichever occurs first. PD before the 3rd administration of ipilimumab not leading to treatment discontinuation does not count as progression for this endpoint. Furthermore, the additional tumor assessment at 20 weeks for patients with PD n.c.s. before week 20 will not be taken into consideration for calculation of this endpoint. Patients without event at the time of analysis and patients starting a new anticancer therapy in the absence of an event will be censored at the date of the last tumor assessment showing non-progression (before the start of the new therapy, if any).
2. Duration of response (DOR) (Time Frame - at weeks 8, 14, 20, 26, and then every 12 weeks up to 2 years.):
DOR is defined as time from the date when a patient first meets the criteria for PR or CR according to RECIST v1.1, until documented progression, relapse or death due to disease progression, whichever occurs first. PD before the 3rd administration of ipilimumab not leading to treatment discontinuation does not count as progression for this endpoint. Furthermore, the additional tumor assessment at 20 weeks for patients with PD n.c.s. before week 20 will not be taken into consideration for calculation of this endpoint. Patients without event at the time of analysis and patients starting a new anticancer therapy in the absence of an event will be censored at the date of the last tumor assessment showing non-progression before the start of the new therapy (if any). DOR will only be analyzed in the subgroup of patients achieving PR or CR during trial treatment.
3. Time to treatment failure (TTF) (Time Frame - at weeks 8, 14, 20, 26, and then every 12 weeks up to 2 years.):
TTF defined as time from registration to treatment discontinuation due to any reason. Patients still on treatment at the time of analysis will be censored at the date of last treatment administration. Furthermore, the additional tumor assessment at 20 weeks for patients with PD n.c.s. before week 20 will not be taken into consideration for calculation of this endpoint.
4. Overall survival (OS) (Time Frame - At weeks 8. 14, 20, 26, then every 12 weeks until 2 years.):
OS is defined as the time from registration until death from any cause. Patients without event at the time of analysis will be censored at the date they were last known to be alive.
5. Adverse events (AEs) (Time Frame - at weeks 8, 14, 20, 26, then every 12 weeks, until 100 days after last dose of treatment.):
AEs are assessed according to NCI CTCAE v4.03.
- nivolumab (Opdivo):
240 mg every 2 weeks during the first 20 weeks, 480 mg every 4 weeks thereafter
- ipilimumab (Yervoy):
After 2 weeks 1mg/kg every 6 weeks
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