OPDIVO Concentrate for solution for infusion Ref.[7411] Active ingredients: Nivolumab

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies
ATC code: L01XC17

Mechanism of action

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to the programmed death-1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Nivolumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands. In syngeneic mouse models, blocking PD-1 activity resulted in decreased tumour growth.

Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in improved anti-tumour responses in metastatic melanoma. In murine syngeneic tumour models, dual blockade of PD-1 and CTLA-4 resulted in synergistic anti-tumour activity.

Clinical efficacy and safety

Based on modelling of dose/exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety between a nivolumab dose of 240 mg every 2 weeks or 3 mg/kg every 2 weeks. Additionally, based on these relationships, there were no clinically significant differences between a nivolumab dose of 480 mg every 4 weeks or 3 mg/kg every 2 weeks in advanced melanoma and RCC.

Melanoma

Treatment of advanced melanoma:

Randomised phase 3 study vs. dacarbazine (CA209066)

The safety and efficacy of nivolumab 3 mg/kg for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209066). The study included adult patients (18 years or older) with confirmed, treatment-naive, Stage III or IV BRAF wild-type melanoma and an ECOG performance-status score of 0 or 1. Patients with active autoimmune disease, ocular melanoma, or active brain or leptomeningeal metastases were excluded from the study.

A total of 418 patients were randomised to receive either nivolumab (n=210) administered intravenously over 60 minutes at 3 mg/kg every 2 weeks or dacarbazine (n=208) at 1000 mg/m² every 3 weeks. Randomisation was stratified by tumour PD-L1 status and M stage (M0/M1a/M1b versus M1c). Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Treatment after disease progression was permitted for patients who had a clinical benefit and did not have substantial adverse effects with the study drug, as determined by the investigator. Tumour assessments, according to the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks for the first year and then every 12 weeks thereafter. The primary efficacy outcome measure was OS. Key secondary efficacy outcome measures were investigator-assessed PFS and objective response rate (ORR).

Baseline characteristics were balanced between the two groups. The median age was 65 years (range: 18-87), 59% were men, and 99.5% were white. Most patients had ECOG performance score of 0 (64%) or 1 (34%). Sixty-one percent of patients had M1c stage disease at study entry. Seventy-four percent of patients had cutaneous melanoma, and 11% had mucosal melanoma; 35% of patients had PD-L1 positive melanoma (≥5% tumour cell membrane expression). Sixteen percent of patients had received prior adjuvant therapy; the most common adjuvant treatment was interferon (9%). Four percent of patients had a history of brain metastasis, and 37% of patients had a baseline LDH level greater than ULN at study entry.

The Kaplan-Meier curves for OS are shown in Figure 1.

Figure 1. Kaplan-Meier curves of OS (CA209066):

The observed OS benefit was consistently demonstrated across subgroups of patients including baseline ECOG performance status, M stage, history of brain metastases, and baseline LDH level. Survival benefit was observed regardless of whether patients had tumours that were designated PD-L1 negative or PD-L1 positive (tumour membrane expression cut off of 5% or 10%).

Data available indicate that the onset of nivolumab effect is delayed such that benefit of nivolumab above chemotherapy may take 2-3 months.

Efficacy results are shown in Table 8.

Table 8. Efficacy Results (CA209066):

Randomised phase 3 study vs. chemotherapy (CA209037)

The safety and efficacy of nivolumab 3 mg/kg for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, open-label study (CA209037). The study included adult patients who had progressed on or after ipilimumab and if BRAF V600 mutation positive had also progressed on or after BRAF kinase inhibitor therapy. Patients with active autoimmune disease, ocular melanoma, active brain or leptomeningeal metastases or a known history of prior ipilimumab-related high-grade (Grade 4 per CTCAE v4.0) adverse reactions, except for resolved nausea, fatigue, infusion reactions, or endocrinopathies, were excluded from the study.

A total of 405 patients were randomised to receive either nivolumab (n=272) administered intravenously over 60 minutes at 3 mg/kg every 2 weeks or chemotherapy (n=133) which consisted of the investigator’s choice of either dacarbazine (1000 mg/m² every 3 weeks) or carboplatin (AUC 6 every 3 weeks) and paclitaxel (175 mg/m² every 3 weeks). Randomisation was stratified by BRAF and tumour PD-L1 status and best response to prior ipilimumab.

The co-primary efficacy outcome measures were confirmed ORR in the first 120 patients treated with nivolumab, as measured by independent radiology review committee (IRRC) using RECIST, version 1.1, and comparison of OS of nivolumab to chemotherapy. Additional outcome measures included duration and timing of response.

The median age was 60 years (range: 23-88). Sixty-four percent of patients were men and 98% were white. ECOG performance scores were 0 for 61% of patients and 1 for 39% of patients. The majority (75%) of patients had M1c stage disease at study entry. Seventy-three percent of patients had cutaneous melanoma and 10% had mucosal melanoma. The number of prior systemic regimen received was 1 for 27% of patients, 2 for 51% of patients, and >2 for 21% of patients. Twenty-two percent of patients had tumours that tested BRAF mutation positive and 50% of patients had tumours that were considered PD-L1 positive. Sixty-four percent of patients had no prior clinical benefit (CR/PR or SD) on ipilimumab. Baseline characteristics were balanced between groups except for the proportions of patients who had a history of brain metastasis (19% and 13% in the nivolumab group and chemotherapy group, respectively) and patients with LDH greater than ULN at baseline (51% and 35%, respectively).

At the time of this final ORR analysis, results from 120 nivolumab-treated patients and 47 chemotherapy-treated patients who had a minimum of 6 months of follow-up were analysed. Efficacy results are presented in Table 9.

Table 9. Best overall response, time and duration of response (CA209037):

Data available indicate that the onset of nivolumab effect is delayed such that benefit of nivolumab above chemotherapy may take 2-3 months.

Updated analysis (24-month follow-up)

Among all randomised patients, the ORR was 27.2% (95% CI: 22.0, 32.9) in the nivolumab group and 9.8% (95% CI: 5.3, 16.1) in the chemotherapy group. Median durations of response were 31.9 months (range: 1.4+ - 31.9) and 12.8 months (range: 1.3+ - 13.6+), respectively. The PFS HR for nivolumab vs. chemotherapy was 1.03 (95% CI: 0.78, 1.36). The ORR and PFS were assessed by IRRC per RECIST version 1.1.

There was no statistically significant difference between nivolumab and chemotherapy in the final OS analysis. The primary OS analysis was not adjusted to account for subsequent therapies, with 54 (40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may be confounded by dropout, imbalance of subsequent therapies and differences in baseline factors. More patients in the nivolumab arm had poor prognostic factors (elevated LDH and brain metastases) than in the chemotherapy arm.

Efficacy by BRAF status:

Objective responses to nivolumab (according to the definition of the co-primary endpoint) were observed in patients with or without BRAF mutation-positive melanoma. The ORRs in the BRAF mutation-positive subgroup were 17% (95% CI: 8.4, 29.0) for nivolumab and 11% (95% CI: 2.4, 29.2) for chemotherapy, and in the BRAF wild-type subgroup were 30% (95% CI: 24.0, 36.7) and 9% (95% CI: 4.6, 16.7), respectively.

The PFS HRs for nivolumab vs. chemotherapy were 1.58 (95% CI: 0.87, 2.87) for BRAF mutation-positive patients and 0.82 (95% CI: 0.60, 1.12) for BRAF wild-type patients. The OS HRs for nivolumab vs. chemotherapy were 1.32 (95% CI: 0.75, 2.32) for BRAF mutation-positive patients and 0.83 (95% CI: 0.62, 1.11) for BRAF wild-type patients.

Efficacy by tumour PD-L1 expression:

Objective responses to nivolumab were observed regardless of tumour PD-L1 expression. However, the role of this biomarker (tumour PD-L1 expression) has not been fully elucidated.

In patients with tumour PD-L1 expression ≥1%, ORR was 33.5% for nivolumab (n=179; 95% CI: 26.7, 40.9) and 13.5% for chemotherapy (n=74; 95% CI: 6.7, 23.5). In patients with tumour PD-L1 expression <1%, ORR per IRRC was 13.0% (n=69; 95% CI: 6.1, 23.3) and 12.0% (n=25; 95% CI: 2.5, 31.2), respectively.

The PFS HRs for nivolumab vs. chemotherapy were 0.76 (95% CI: 0.54, 1.07) in patients with tumour PD-L1 expression ≥1% and 1.92 (95% CI: 1.05, 3.5) in patients with tumour PD-L1 expression <1%.

The OS HRs for nivolumab vs. chemotherapy were 0.69 (95% CI: 0.49, 0.96) in patients with tumour PD-L1 expression ≥1% and 1.52 (95% CI: 0.89, 2.57) in patients with tumour PD-L1 expression <1%.

These subgroup analyses should be interpreted with caution given the small size of the subgroups and lack of statistically significant difference in OS in the all randomised population.

Open-label phase 1 dose-escalation study (MDX1106-03)

The safety and tolerability of nivolumab were investigated in a phase 1, open-label dose-escalation study in various tumour types, including malignant melanoma. Of the 306 previously treated patients enrolled in the study, 107 had melanoma and received nivolumab at a dose of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg for a maximum of 2 years. In this patient population, objective response was reported in 33 patients (31%) with a median duration of response of 22.9 months (95% CI: 17.0, NR). The median PFS was 3.7 months (95% CI: 1.9, 9.3). The median OS was 17.3 months (95% CI: 12.5, 37.8), and the estimated OS rates were 42% (95% CI: 32, 51) at 3 years, 35% (95% CI: 26, 44) at 4 years, and 34% (95% CI: 25, 43) at 5 years (minimum follow-up of 45 months).

Single-arm phase 2 study (CA209172)

Study CA209172 was a single-arm, open label study of nivolumab monotherapy in patients with stage III (unresectable) or stage IV metastatic melanoma after prior treatment containing an anti- CTLA-4 monoclonal antibody. Safety was the primary endpoint and efficacy was a secondary endpoint. Of the 1008 treated patients, 103 (10%) had ocular/uveal melanoma, 66 (7%) had an ECOG performance score of 2, 165 (16%) had asymptomatic treated and untreated CNS metastases, 13 (1.3%) had treated leptomeningeal metastases, 25 (2%) had autoimmune disease, and 84 (8%) had Grade 3-4 immune-related AEs with prior anti-CTLA-4 therapy. No new safety signals were identified in all treated patients and the overall safety profile of nivolumab was similar across subgroups. Efficacy results based on investigator-assessed response rates at week 12 are presented in Table 10 below.

Table 10. Response rate at week 12 – all response evaluable patients and by subgroup (CA209172):

^a Responses were assessed per RECIST 1.1 for 588/1008 (58.3%) of patients who continued treatment through week 12 and had a follow-up scan at week 12.

Randomised phase 3 study of nivolumab in combination with ipilimumab or nivolumab as monotherapy vs. ipilimumab as monotherapy (CA209067)

The safety and efficacy of nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg or nivolumab 3 mg/kg vs. ipilimumab 3 mg/kg monotherapy for the treatment of advanced (unresectable or metastatic) melanoma were evaluated in a phase 3, randomised, double-blind study (CA209067). The differences between the two nivolumab-containing groups were evaluated descriptively. The study included adult patients with confirmed unresectable Stage III or Stage IV melanoma. Patients were to have ECOG performance status score of 0 or 1. Patients who had not received prior systemic anticancer therapy for unresectable or metastatic melanoma were enrolled. Prior adjuvant or neoadjuvant therapy was allowed if it was completed at least 6 weeks prior to randomisation. Patients with active autoimmune disease, ocular/uveal melanoma, or active brain or leptomeningeal metastases were excluded from the study.

A total of 945 patients were randomised to receive nivolumab in combination with ipilimumab (n=314), nivolumab monotherapy (n=316), or ipilimumab monotherapy (n=315). Patients in the combination arm received nivolumab 1 mg/kg over 60 minutes and ipilimumab 3 mg/kg over 90 minutes administered intravenously every 3 weeks for the first 4 doses, followed by nivolumab 3 mg/kg as monotherapy every 2 weeks. Patients in the nivolumab monotherapy arm received nivolumab 3 mg/kg every 2 weeks. Patients in the comparator arm received ipilimumab 3 mg/kg and nivolumab-matched placebo intravenously every 3 weeks for 4 doses followed by placebo every 2 weeks. Randomisation was stratified by PD-L1 expression (≥5% vs. <5% tumour cell membrane expression), BRAF status, and M stage per the American Joint Committee on Cancer (AJCC) staging system. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments were conducted 12 weeks after randomisation then every 6 weeks for the first year, and every 12 weeks thereafter. The co-primary outcome measures were progression-free survival and OS. ORR and the duration of response were also assessed.

Baseline characteristics were balanced across the three treatment groups. The median age was 61 years (range: 18 to 90 years), 65% of patients were men, and 97% were white. ECOG performance status score was 0 (73%) or 1 (27%). The majority of the patients had AJCC Stage IV disease (93%); 58% had M1c disease at study entry. Twenty-two percent of patients had received prior adjuvant therapy. Thirty-two percent of patients had BRAF mutation-positive melanoma; 26.5% of patients had PD-L1 ≥5% tumour cell membrane expression. Four percent of patients had a history of brain metastasis, and 36% of patients had a baseline LDH level greater than ULN at study entry. Among patients with quantifiable tumour PD-L1 expression, the distribution of patients was balanced across the three treatment groups. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.

PFS results (with minimum follow up of 18 months) are shown in Figure 2 (all randomised population), Figure 3 (at the tumour PD-L1 5% cut off), and Figure 4 (at the tumour PD-L1 1% cut off).

Figure 2. Progression-free survival (CA209067):

Figure 3. Progression-free survival by PD-L1 expression: 5% cut off (CA209067):

Figure 4. Progression-free survival by PD-L1 expression: 1% cut off (CA209067):

The final OS analysis occurred when all patients had a minimum follow-up of 28 months. OS results at an additional analysis undertaken at a minimum follow-up of 36 months show outcomes consistent with the original analysis. OS results from this follow-up analysis are shown in Figure 5 (all randomised), Figure 6 (at the tumour PD-L1 1% cut off), and Table 11 (at the tumour PD-L1 5% cut off).

The OS analysis was not adjusted to account for subsequent therapies received. Subsequent systemic therapy was received by 31.8%, 44.3%, and 62.2% of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively. Subsequent immunotherapy (including anti-PD1 therapy, anti-CTLA-4 antibody, or other immunotherapy) was received by 14.6%, 29.1%, and 44.1% of patients in the combination, nivolumab monotherapy, and ipilimumab arms, respectively.

Figure 5. Overall survival (CA209067) - Minimum follow-up of 36 months:

Figure 6. Overall survival by PD-L1 expression: 1% cut off (CA209067) - Minimum follow-up of 36 months:

Table 11. Summary of overall survival by PD-L1 expression: 5% cut off – CA209067 – Minimum follow-up of 36 months:

Table 12. Objective response (CA209067):

Both nivolumab-containing arms demonstrated a significant PFS and OS benefit and greater ORR compared with ipilimumab alone. The observed PFS results at 18 months of follow-up and ORR and OS results at 28 months of follow-up were consistently demonstrated across subgroups of patients including baseline ECOG performance status, BRAF status, M stage, age, history of brain metastases, and baseline LDH level. This observation was maintained with the OS results with a minimum follow-up of 36 months.

Among 128 patients who discontinued nivolumab in combination with ipilimumab due to adverse reaction after 18 months of follow-up, median PFS was 16.7 months (95% CI: 10.2, NA). Among 131 patients who discontinued the combination due to adverse reaction after 28 months of follow-up, the ORR was 71% (93/131) with 20% (26/131) achieving a complete response and median OS was not reached.

Both nivolumab-containing arms demonstrated greater objective response rates than ipilimumab regardless of PD-L1 expression levels. ORRs were higher for the combination of nivolumab and ipilimumab relative to nivolumab monotherapy across tumour PD-L1 expression levels (Table 12) after 28 months of follow-up, with a best overall response of complete response correlating to an improved survival rate.

After 28 months of follow-up, median durations of response for patients with tumour PD-L1 expression level ≥5% were not reached (range: 0+ - 31.6+) in the combination arm, not reached (range: 2.8-30.6+) in the nivolumab monotherapy arm and not reached (range: 1.4-30.6+) in the ipilimumab arm. At tumour PD-L1 expression <5%, median durations of response were not reached (range: 0+ - 33.3+) in the combination arm, not reached (range: 0+ - 32.3+) in the nivolumab monotherapy arm and 18.2 months (range: 0.0+ - 31.5+) in the ipilimumab monotherapy arm.

No clear cut off for PD-L1 expression can reliably be established when considering the relevant endpoints of tumour response and PFS and OS. Results from exploratory multivariate analyses identified patient and tumour characteristics (ECOG performance status, M stage, baseline LDH, BRAF mutation status, PD-L1 status, and gender) which might contribute to the survival outcome.

Efficacy by BRAF status: After18 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients randomised to nivolumab in combination with ipilimumab had a median PFS of 15.5 months (95% CI: 8.0, NA) and 11.3 months (95% CI: 8.3, 22.2), while those in the nivolumab monotherapy arm had a median PFS of 5.6 months (95% CI: 2.8, 9.3) and 7.1 months (95% CI: 4.9, 14.3), respectively. After 28 months of follow-up, BRAF[V600] mutation-positive and BRAF wild-type patients randomised to nivolumab in combination with ipilimumab had an ORR of 67.6% (95% CI: 57.7, 76.6; n=102) and 54.7% (95% CI: 47.8, 61.5; n=212), while those in the nivolumab monotherapy arm had an ORR of 36.7% (95% CI: 27.2, 47.1; n=98) and 48.2% (95% CI: 41.4, 55.0; n=218), respectively. After 28 months of follow-up, median OS was not reached in either of the nivolumab containing arms regardless of BRAF status. The OS HRs for nivolumab in combination with ipilimumab vs. nivolumab monotherapy were 0.71 (95% CI: 0.45, 1.13) for BRAF[V600] mutation-positive patients and 0.97 (95% CI: 0.74, 1.28) for BRAF wild-type patients.

Randomised phase 2 study of nivolumab in combination with ipilimumab and ipilimumab (CA209069)

Study CA209069 was a randomised, Phase 2, double-blind study comparing the combination of nivolumab and ipilimumab with ipilimumab alone in 142 patients with advanced (unresectable or metastatic) melanoma with similar inclusion criteria to study CA209067 and the primary analysis in patients with BRAF wild-type melanoma (77% of patients). Investigator assessed ORR was 61% (95% CI: 48.9, 72.4) in the combination arm (n=72) versus 11% (95% CI: 3.0, 25.4) for the ipilimumab arm (n=37). The estimated 2 and 3 year OS rates were 68% (95% CI: 56, 78) and 61% (95% CI: 49, 71), respectively, for the combination (n=73) and 53% (95% CI: 36, 68) and 44% (95% CI: 28, 60), respectively, for ipilimumab (n=37).

Adjuvant treatment of melanoma

Randomised phase 3 study of nivolumab vs ipilimumab 10 mg/kg (CA209238)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of patients with completely resected melanoma were evaluated in a phase 3, randomised, double-blind study (CA209238). The study included adult patients, who had an ECOG performance status score of 0 or 1, with Stage IIIB/C or Stage IV American Joint Committee on Cancer (AJCC), 7^th edition, histologically confirmed melanoma that is completely surgically resected. Per the AJCC 8^th edition, this corresponds to patients with lymph node involvement or metastases. Patients were enrolled regardless of their tumour PD-L1 status. Patients with prior autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma (except patients with surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥6 months prior to randomisation) prior therapy with, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways), were excluded from the study.

A total of 906 patients were randomised to receive either nivolumab 3 mg/kg (n=453) administered every 2 weeks or ipilimumab 10 mg/kg (n=453) administered every 3 weeks for 4 doses then every 12 weeks beginning at week 24 for up to 1 year. Randomisation was stratified by tumour PD-L1 expression (≥5% vs. <5%/indeterminate), and stage of disease per the AJCC staging system. Tumour assessments were conducted every 12 weeks for the first 2 years then every 6 months thereafter. The primary endpoint was recurrence-free survival (RFS). RFS, assessed by investigator, was defined as the time between the date of randomisation and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death due to any cause, whichever occurred first.

Baseline characteristics were generally balanced between the two groups. The median age was 55 years (range: 18-86), 58% were men, and 95% were white. Baseline ECOG performance status score was 0 (90%) or 1 (10%). The majority of patients had AJCC Stage III disease (81%), and 19% had Stage IV disease. Forty-eight percent of patients had macroscopic lymph nodes and 32% had tumour ulceration. Forty-two percent of patients were BRAF V600 mutation positive while 45% were BRAF wild type and 13% BRAF were status unknown. For tumour PD-L1 expression, 34% of patients had PD-L1 expression ≥5% and 62% had <5% as determined by clinical trial assay. Among patients with quantifiable tumour PD-L1 expression, the distribution of patients was balanced across the treatment groups. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.

Minimum follow-up was approximately 24 months. OS was not mature at the time of this analysis. RFS results are shown in Table 13 and Figure 7 (all randomised population).

Table 13. Efficacy results (CA209238):

Figure 7. Recurrence-free Survival (CA209238):

The trial demonstrated a statistically significant improvement in RFS for patients randomised to the nivolumab arm compared with the ipilimumab 10 mg/kg arm. RFS benefit was consistently demonstrated across subgroups, including tumour PD-L1 expression, BRAF status, and stage of disease.

Quality of life (QoL) with nivolumab remained stable and close to baseline values during treatment, as assessed by valid and reliable scales like the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EQ-5D utility index and visual analog scale (VAS).

Non-Small Cell Lung Cancer

Squamous NSCLC:

Randomised phase 3 study vs. docetaxel (CA209017)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced or metastatic squamous NSCLC were evaluated in a phase 3, randomised, open-label study (CA209017). The study included patients (18 years or older) who have experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen and an ECOG performance status score of 0 or 1. Patients were enrolled regardless of their tumour PD-L1 status. Patients with active autoimmune disease, symptomatic interstitial lung disease, or active brain metastases were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents.

A total of 272 patients were randomised to receive either nivolumab 3 mg/kg (n=135) administered intravenously over 60 minutes every 2 weeks or docetaxel (n=137) 75 mg/m² every 3 weeks. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments, according to the RECIST, version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks thereafter. The primary efficacy outcome measure was OS. Key secondary efficacy outcome measures were investigator-assessed ORR and PFS. In addition, symptom improvement and overall health status were assessed using the Lung Cancer Symptom Score (LCSS) average symptom burden index and the EQ-5D Visual Analogue Scale (EQ-VAS), respectively.

Baseline characteristics were generally balanced between the two groups. The median age was 63 years (range: 39-85) with 44% 65 years of age and 11% 75 years of age. The majority of patients were white (93%) and male (76%). Thirty-one percent had progressive disease reported as the best response to their most recent prior regimen and 45% received nivolumab within 3 months of completing their most recent prior regimen. Baseline ECOG performance status score was 0 (24%) or 1 (76%).

The Kaplan-Meier curves for OS are shown in Figure 8.

Figure 8. Kaplan-Meier curves of OS (CA209017):

The observed OS benefit was consistently demonstrated across subgroups of patients. Survival benefit was observed regardless of whether patients had tumours that were designated PD-L1 negative or PD-L1 positive (tumour membrane expression cut off of 1%, 5% or 10%). However, the role of this biomarker (tumour PD-L1 expression) has not been fully elucidated. With a minimum of 24.2 months follow-up, OS benefit remains consistently demonstrated across subgroups.

Study CA209017 included a limited number of patients ≥75 years (11 in the nivolumab group and 18 in the docetaxel group). Nivolumab showed numerically less effect on OS (HR 1.85; 95% CI: 0.76, 4.51), PFS (HR=1.76; 95%-CI: 0.77, 4.05) and ORR (9.1% vs. 16.7%). Because of the small sample size, no definitive conclusions can be drawn from these data.

Efficacy results are shown in Table 14.

Table 14. Efficacy results (CA209017):

The rate of disease-related symptom improvement, as measured by LCSS, was similar between the nivolumab group (18.5%) and the docetaxel group (21.2%). The average EQ-VAS increased over time for both treatment groups, indicating better overall health status for patients remaining on treatment.

Single-arm phase 2 study (CA209063)

Study CA209063 was a single-arm, open-label study conducted in 117 patients with locally advanced or metastatic squamous NSCLC after two or more lines of therapy; otherwise similar inclusion criteria as study CA209017 were applied. Nivolumab 3 mg/kg showed an ORR of 14.5% (95% CI: 8.7,22.2%), a median OS of 8.21 months (95% CI: 6.05,10.9), and a median PFS of 1.87 months (95% CI 1.77,3.15). The PFS was measured by RECIST, version 1.1. The estimated 1-year survival rate was 41%.

Single-arm phase 2 study (CA209171)

Study CA209171 was a single-arm, open label study of nivolumab monotherapy in patients with previously treated advanced or metastatic squamous NSCLC. Safety was the primary endpoint and efficacy was a secondary endpoint. Of the 811 treated patients, 103 (13%) had an ECOG performance score of 2, 686 (85%) were <75 years old and 125 (15%) were ≥75 years old. No new safety signals were identified in all treated patients and the overall safety profile of nivolumab was similar across subgroups. Efficacy results based on investigator-assessed ORR are presented in Table 15 below.

Table 15. ORR based on response evaluable patients – total and by subgroup (CA209171):

^a includes confirmed and unconfirmed responses, scans were mandatory only at week 8/9 and week 52.
^b CR+PR, confidence interval based on the Clopper and Pearson method

Non-squamous NSCLC:

Randomised phase 3 study vs. docetaxel (CA209057)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced or metastatic non-squamous NSCLC were evaluated in a phase 3, randomised, open-label study (CA209057). The study included patients (18 years or older) who have experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen which may have included maintenance therapy and who had an ECOG performance status score of 0 or 1. An additional line of TKI therapy was allowed for patients with known EGFR mutation or ALK translocation. Patients were enrolled regardless of their tumour PD-L1 status. Patients with active autoimmune disease, symptomatic interstitial lung disease, or active brain metastases were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents.

A total of 582 patients were randomised to receive either nivolumab 3 mg/kg administered intravenously over 60 minutes every 2 weeks (n=292) or docetaxel 75 mg/m² every 3 weeks (n=290). Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments were conducted according to the RECIST version 1.1. The primary efficacy outcome measure was OS. Key secondary efficacy outcome measures were investigator-assessed ORR and PFS. Additional prespecified subgroup analyses were conducted to evaluate the efficacy of tumour PD-L1 expression at predefined levels of 1%, 5% and 10%. Assessment according to discrete PD-L1 expression intervals were not included in the prespecified analyses due to the small sample sizes within the intervals.

Pre-study tumour tissue specimens were systematically collected prior to randomisation in order to conduct pre-planned analyses of efficacy according to tumour PD-L1 expression. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.

The median age was 62 years (range: 21 to 85) with 34% 65 years of age and 7% 75 years of age. The majority of patients were white (92%) and male (55%). Baseline ECOG performance status was 0 (31%) or 1 (69%). Seventy-nine percent of patients were former/current smokers.

The Kaplan-Meier curves for OS are shown in Figure 9.

Figure 9. Kaplan-Meier curves of OS (CA209057):

The trial demonstrated a statistically significant improvement in OS for patients randomised to nivolumab as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis). Efficacy results are shown in Table 16.

Table 16. Efficacy results (CA209057):

Quantifiable tumour PD-L1 expression was measured in 79% of patients in the nivolumab group and 77% of patients in the docetaxel group. Tumour PD-L1 expression levels were balanced between the two treatment groups (nivolumab vs. docetaxel) at each of the predefined tumour PD-L1 expression levels of ≥1% (53% vs. 55%), ≥5% (41% vs. 38%), or ≥10% (37% vs. 35%).

Patients with tumour PD-L1 expression by all predefined expression levels in the nivolumab group demonstrated greater likelihood of improved survival compared to docetaxel, whereas survival was similar to docetaxel in patients with low or no tumour PD-L1 expression. In terms of ORR, increasing PD-L1 expression was associated with larger ORR. Comparable to the overall population, median duration of response was increased with nivolumab vs. docetaxel for patients with no PD-L1 expression (18.3 months vs. 5.6 months) and for patients with PD-L1 expression (16.0 months vs. 5.6 months).

Table 17 summarises results of ORR and OS by tumour PD-L1 expression.

Table 17. ORR and OS by tumour PD-L1 expression (CA209057):

A higher proportion of patients experienced death within the first 3 months in the nivolumab arm (59/292, 20.2%) as compared to the docetaxel arm (44/290, 15.2%). Results of a post-hoc, exploratory multivariate analysis indicated that nivolumab-treated patients with poorer prognostic features and/or aggressive disease when combined with lower (e.g. <50%) or no tumour PD-L1 expression may be at higher risk of death within the first 3 months.

In subgroup analyses, survival benefit compared to docetaxel was not shown for patients who were never-smokers or whose tumours harboured EGFR activating mutations; however, due to the small numbers of patients, no definitive conclusions can be drawn from these data.

Renal Cell Carcinoma

Randomised phase 3 study of nivolumab as monotherapy vs. everolimus (CA209025)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of advanced RCC with a clear cell component was evaluated in a Phase 3, randomised, open-label study (CA209025). The study included patients (18 years or older) who have experienced disease progression during or after 1 or 2 prior anti-angiogenic therapy regimens and no more than 3 total prior systemic treatment regimens. Patients had to have a Karnofsky Performance Score (KPS) 70%. This study included patients regardless of their tumour PD-L1 status. Patients with any history of or concurrent brain metastases, prior treatment with an mammalian target of rapamycin (mTOR) inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study.

A total of 821 patients were randomised to receive either nivolumab 3 mg/kg (n=410) administered intravenously over 60 minutes every 2 weeks or everolimus (n=411) 10 mg daily, administered orally. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 8 weeks after randomisation and continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. Tumour assessments were continued after treatment discontinuation in patients who discontinued treatment for reasons other than progression. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug as determined by the investigator. The primary efficacy outcome measure was OS. Secondary efficacy assessments included investigator-assessed ORR and PFS.

Baseline characteristics were generally balanced between the two groups. The median age was 62 years (range: 18-88) with 40% 65 years of age and 9% 75 years of age. The majority of patients were male (75%) and white (88%), all Memorial Sloan Kettering Cancer Center (MSKCC) risk groups were represented, and 34% and 66% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. The majority of patients (72%) were treated with one prior anti-angiogenic therapy. The median duration of time from initial diagnosis to randomisation was 2.6 years in both the nivolumab and everolimus groups. The median duration of treatment was 5.5 months (range: 0 – 29.6+ months) in nivolumab-treated patients and was 3.7 months (range: 6 days-25.7+ months) in everolimus-treated patients. Nivolumab was continued beyond progression in 44% of patients.

The Kaplan-Meier curves for OS are shown in Figure 10.

Figure 10. Kaplan-Meier curves of OS (CA209025):

The trial demonstrated a statistically significant improvement in OS for patients randomised to nivolumab as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis) (Table 18 and Figure 10). OS benefit was observed regardless of tumour PD-L1 expression level. Efficacy results are shown in Table 18.

Table 18. Efficacy results (CA209025):

The median time to onset of objective response was 3.5 months (range: 1.4-24.8 months) after the start of nivolumab treatment. Fourty-nine (47.6%) responders had ongoing responses with a duration ranging from 0.0 – 27.6+ months.

Overall survival could be accompanied by an improvement over time in disease related symptoms and non-disease specific QoL as assessed using valid and reliable scales in the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and the EuroQoL EQ-5D. Apparently meaningful symptom improvement (MID=2 point change in FKSI-DRS score; p<0.001) and time to improvement (HR=1.66 (1.33,2.08), p<0.001) were significantly better for patients on the nivolumab arm. While both arms of the study received active therapy, the QoL data should be interpreted in the context of the open-label study design and therefore cautiously taken.

Phase 3b/4 safety study (CA209374)

Additional safety and descriptive efficacy data are available from study CA209374, an open-label Phase 3b/4 safety study of nivolumab monotherapy (treated with 240 mg every 2 weeks) for the treatment of patients with advanced or metastatic RCC (n=142), including 44 patients with non-clear cell histology.

In subjects with non-clear cell histology, at a minimum follow-up of approximately 16.7 months ORR and median duration of response were 13.6% and 10.2 months, respectively. Clinical activity was observed regardless of tumour PD-L1 expression status.

Randomised phase 3 study of nivolumab in combination with ipilimumab vs. sunitinib (CA209214)

The safety and efficacy of nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg for the treatment of advanced/metastatic RCC was evaluated in a phase 3, randomised, open-label study (CA209214). The study included patients (18 years or older) with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component. The primary efficacy population included those intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the International Metastatic RCC Database Consortium (IMDC) criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status <80%, haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal). This study included patients regardless of their tumour PD-L1 status. Patients with Karnofsky performance status <70% and patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients were stratified by IMDC prognostic score and region.

A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab 3 mg/kg (n=425) administered intravenously over 60 minutes in combination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) 50 mg daily, administered orally for 4 weeks followed by 2 weeks off, every cycle. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 12 weeks after randomisation and continued every 6 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a clinical benefit and was tolerating study drug as determined by the investigator. The primary efficacy outcome measures were OS, ORR and PFS as determined by a Blinded Independent Central Review (BICR) in intermediate/poor risk patients.

Baseline characteristics were generally balanced between the two groups. The median age was 61 years (range: 21-85) with 38% 65 years of age and 8% 75 years of age. The majority of patients were male (73%) and white (87%), and 31% and 69% of patients had a baseline KPS of 70 to 80% and 90 to 100%, respectively. The median duration of time from initial diagnosis to randomisation was 0.4 years in both the nivolumab 3 mg/kg in combination with ipilimumab 1 mg/kg and sunitinib groups. The median duration of treatment was 7.9 months (range: 1 day-21.4+ months) in nivolumab with ipilimumab- treated patients and was 7.8 months (range: 1 days-20.2+ months) in sunitinib- treated patients. Nivolumab with ipilimumab was continued beyond progression in 29% of patients.

The Kaplan-Meier curves for OS (with a minimum follow-up of 24 months) in intermediate/poor risk patients are shown in Figure 11.

Figure 11. Kaplan-Meier curves of OS in intermediate/poor risk patients (CA209214):

In intermediate/poor-risk patients, OS benefit was observed in the nivolumab in combination with ipilimumab arm vs. sunitinib regardless of tumour PD-L1 expression. Median OS for tumour PD-L1 expression ≥1% was not reached for nivolumab in combination with ipilimumab, and was 19.61 months in the sunitinib arm (HR=0.52; 95% CI: 0.34, 0.78). For tumour PD-L1 expression <1%, the median OS was 34.7 months for the nivolumab in combination with ipilimumab, and was 32.2 months in the sunitinib arm (HR=0.70; 95% CI: 0.54, 0.92).

CA209214 also randomised 249 favourable risk patients as per IMDC criteria to nivolumab plus ipilimumab (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the primary efficacy population. OS in favourable risk patients receiving nivolumab plus ipilimumab compared to sunitinib had a hazard ratio of 1.13 (95% CI: 0.64, 1.99; p=0.6710).

There are no data on the use of nivolumab in combination with ipilimumab in patients with only a non clear-cell histology in first line RCC.

Efficacy results for the intermediate/poor risk patients from the primary analysis (minimum follow-up 17.5 months) are shown in Table 19.

Table 19. Efficacy results in intermediate/poor risk patients (CA209214):

An updated OS analysis was performed when all patients had a minimum follow-up of 24 months (see figure 11). At the time of this analysis, the hazard ratio was 0.66; (99.8% CI 0.48-0.91) with 166/425 events in the combination arm and 209/422 events in the sunitinib arm. At 18 months, the OS rate was 74.3 (95% CI 69.8-78.2) for nivolumab in combination with ipilimumab and 59.9 (95% CI 54.9-64.5) for sunitinib. At 24 months, the OS rate was 66.5 (95% CI 61.8-70.9) for nivolumab in combination with ipilimumab and 52.9 (95% CI 47.9-57.7) for sunitinib.

Patients ≥75 years of age represented 8% of all intermediate/poor risk patients in CA209214, and the combination of nivolumab and ipilimumab showed numerically less effect on OS (HR 0.97, 95% CI: 0.48, 1.95) in this subgroup versus the overall population. Because of the small size of this subgroup, no definitive conclusions can be drawn from these data.

Classical Hodgkin Lymphoma

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of relapsed or refractory cHL following ASCT was evaluated in two multi-centre, open-label, single-arm studies (CA209205 and CA209039).

CA209205 is an ongoing Phase 2, open-label, multi-cohort, single-arm study of nivolumab in cHL. It includes 243 patients who had ASCT; Cohort A included 63 (26%) patients who were brentuximab vedotin naïve; Cohort B included 80 (33%) patients who had received brentuximab vedotin after ASCT failure; and Cohort C included 100 (41%) patients who had received brentuximab vedotin before and/or after ASCT out of which 33 (14%) patients received brentuximab vedotin only prior to ASCT. All patients received nivolumab 3 mg/kg monotherapy intravenously over 60 minutes every 2 weeks. The first tumour assessments were conducted 9 weeks after the start of treatment and continued thereafter until disease progression or treatment discontinuation. The primary efficacy outcome measure was ORR as determined by an IRRC. Additional efficacy measures included duration of response, PFS and OS.

CA209039 is a Phase 1b open-label, multi-centre, dose-escalation, and multidose study of nivolumab in relapsed/refractory hematologic malignancies, including 23 patients with cHL treated with nivolumab 3 mg/kg monotherapy; amongst which, 15 patients received prior brentuximab vedotin treatment as a salvage therapy following ASCT, similar to Cohort B of study CA209205. The first tumour assessments were conducted 4 weeks after the start of treatment and continued thereafter until disease progression or treatment discontinuation. Efficacy assessments included investigator-assessed ORR, retrospectively evaluated by an IRRC, and duration of response.

Data from the 80 patients from CA209205 Cohort B and from the 15 patients from CA209039 who received prior brentuximab vedotin treatment following ASCT were integrated. Additional data from 100 patients from CA209205 Cohort C who received brentuximab before and/or after ASCT are also presented. Baseline characteristics were similar across the two studies and cohorts (see Table 20 below).

Table 20. Baseline patient characteristics in CA209205 Cohort B, Cohort C and CA209039:

^a 18/80 (22.5%) of the patients in CA209205 Cohort B presented B-Symptoms at baseline.
^b 25/100 (25%) of the patients in CA209205 Cohort C presented B-Symptoms at baseline.

Efficacy from both studies was evaluated by the same IRRC. Results are shown in Table 21.

Table 21. Efficacy results in patients with relapsed/refractory classical Hodgkin lymphoma:

⁺ denotes a censored observation.
^a Follow-up was ongoing at the time of data submission.
^b Data unstable due to the limited duration of response for Cohort B resulting from censoring.
NE = non-estimable

Longer follow-up data from Cohort B (minimum 20.5 months) and efficacy of Cohort C from CA209205 are presented below in Table 22.

Table 22. Updated efficacy results in patients with relapsed/refractory classical Hodgkin lymphoma from longer follow up of study CA209205:

⁺ denotes a censored observation.
^a Follow-up was ongoing at the time of data submission.
Patients in Cohort C (n=33) who have received brentuximab vedotin only prior to ASCT had ORR of 70% (95% CI: 51, 84), CR of 15% (95% CI: 5, 32), PR of 55% (95% CI: 36, 72). Median duration of response was 13.2 months (95% CI: 8.2, NE)
^c Determined for subjects with CR or PR
NE = non-estimable

B-symptoms were present in 22% (53/243) of the patients in CA209205 at baseline. Nivolumab treatment resulted in rapid resolution of B-symptoms in 88.7% (47/53) of the patients, with a median time to resolution of 1.9 months.

In a post-hoc analysis of the 80 patients in CA209205 Cohort B, 37 had no response to prior brentuximab vedotin treatment. Among these 37 patients, treatment with nivolumab resulted in an ORR of 59.5% (22/37). The median duration of response is 18.0 months (6.6, NE) for the 22 responders to nivolumab who had failed to achieve response with prior brentuximab vedotin treatment.

Squamous Cell Cancer of the Head and Neck

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of metastatic or recurrent SCCHN were evaluated in a phase 3, randomised, open-label study (CA209141). The study included patients (18 years or older), with histologically confirmed recurrent or metastatic SCCHN (oral cavity, pharynx, larynx), stage III/IV and not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy) and who have experienced disease progression during or within 6 months of receiving platinum-based therapy regimen and had an ECOG performance status score of 0 or 1. Prior platinum-based therapy was administered in either the adjuvant, neo-adjuvant, primary, recurrent, or metastatic setting. Patients were enrolled regardless of their tumour PD-L1 or human papilloma virus (HPV) status. Patients with active autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary, salivary gland or non-squamous histologies (e.g. mucosal melanoma), or active brain or leptomeningeal metastases were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents.

A total of 361 patients were randomised to receive either nivolumab 3 mg/kg (n=240) administered intravenously over 60 minutes every 2 weeks or investigator’s choice of either cetuximab (n=15), 400 mg/m² loading dose followed by 250 mg/m² weekly or methotrexate (n=52) 40 to 60 mg/m² weekly, or docetaxel (n=54) 30 to 40 mg/m² weekly. Randomisation was stratified by prior cetuximab treatment. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Tumour assessments, according to RECIST version 1.1, were conducted 9 weeks after randomisation and continued every 6 weeks thereafter. Treatment beyond initial investigator-assessed RECIST version 1.1-defined progression was permitted in patients receiving nivolumab, if the patient had a clinical benefit and was tolerating study drug, as determined by the investigator. The primary efficacy outcome measure was OS. Key secondary efficacy outcome measures were investigator-assessed PFS and ORR. Additional prespecified subgroup analyses were conducted to evaluate the efficacy by tumour PD-L1 expression at predefined levels of 1%, 5%, and 10%.

Pre-study tumour tissue specimens were systematically collected prior to randomisation in order to conduct pre-planned analyses of efficacy according to tumour PD-L1 expression. Tumour PD-L1 expression was determined using the PD-L1 IHC 28-8 pharmDx assay.

Baseline characteristics were generally balanced between the two groups. The median age was 60 years (range: 28-83) with 31% ≥65 years of age and 5% ≥75 years of age, 83% were male, and 83% were white. Baseline ECOG performance status score was 0 (20%) or 1 (78%), 77% were former/current smokers, 90% had Stage IV disease, 66% had two or more lesions, 45%, 34% and 20% received 1, 2, or 3 or more prior lines of systemic therapy, respectively, and 25% were HPV-16 status positive.

With a minimum follow-up of 11.4 months, the trial demonstrated a statistically significant improvement in OS for patients randomised to nivolumab as compared with investigator’s choice. The Kaplan-Meier curves for OS are shown in Figure 12. Efficacy results are shown in Table 23.

Figure 12. Kaplan-Meier curves of OS (CA209141):

Table 23. Efficacy results (CA209141):

Quantifiable tumour PD-L1 expression was measured in 67% of patients in the nivolumab group and 82% of patients in the investigator’s choice group. Tumour PD-L1 expression levels were balanced between the two treatment groups (nivolumab vs. investigator’s choice) at each of the predefined tumour PD-L1 expression levels of ≥1% (55% vs. 62%), ≥5% (34% vs. 43%), or ≥10% (27% vs. 34%).

Patients with tumour PD-L1 expression by all predefined expression levels in the nivolumab group demonstrated greater likelihood of improved survival compared to investigator’s choice. The magnitude of OS benefit was consistent for ≥1%, ≥5% or ≥10% tumour PD-L1 expression levels (see Table 24).

Table 24. OS by tumour PD-L1 expression (CA209141):

In an exploratory post-hoc analysis using a non-validated assay, both tumour cell PD-L1 expression and tumour-associated immune cell (TAIC) PD-L1 expression were analysed in relation to the magnitude of treatment effect of nivolumab compared to investigator’s choice. This analysis showed that not only tumour cell PD-L1 expression but also TAIC PD-L1 expression appeared to be associated with benefit from nivolumab relative to investigator’s choice (see Table 25). Due to the small numbers of patients in the subgroups, and exploratory nature of the analysis, no definitive conclusions can be drawn from these data.

Table 25. Efficacy by tumour cell and TAIC PD-L1 expression (CA209141):

^a OS and PFS were estimated using Kaplan-Meier method.
^b Hazard ratio in each subgroup derived from a Cox proportional hazards model with treatment as the only covariate.
^c Confidence interval for ORR calculated using the Clopper-Pearson method.
^d PD-L1+ TAIC in the tumour microenvironment were qualitatively assessed, and characterised as “numerous”, “intermediate”, and “rare” based on pathologist assessments. “Numerous” and “intermediate” groups were combined to define the “abundant” group.

Patients with investigator-assessed primary site of oropharyngeal cancer were tested for HPV (determined by p16 immunohistochemistry [IHC]). OS benefit was observed regardless of HPV status (HPV-positive: HR=0.63; 95% CI: 0.38, 1.04, HPV-negative: HR=0.64; 95% CI: 0.40, 1.03, and HPV-unknown: HR=0.78; 95% CI: 0.55, 1.10).

Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30, EORTC QLQ-H&N35, and 3-level EQ-5D. Over 15 weeks of follow-up, patients treated with nivolumab exhibited stable PROs, while those assigned to investigator’s choice therapy exhibited significant declines in functioning (e.g. physical, role, social) and health status as well as increased symptomatology (e.g. fatigue, dyspnoea, appetite loss, pain, sensory problems, social contact problems). The PRO data should be interpreted in the context of the open-label study design and therefore taken cautiously.

Urothelial Carcinoma

Open-label phase 2 study (CA209275)

The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma was evaluated in a phase 2, multicentre, open- label, single-arm study (CA209275). The study included patients (18 years or older) who had disease progression during or following platinum-containing chemotherapy for advanced or metastatic disease or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Patients had an ECOG performance status score of 0 or 1 and were enrolled regardless of their tumour PD-L1 status. Patients with active brain metastases or leptomeningeal metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients that received more than 2 prior lines of chemotherapy with liver metastases were excluded.

A total of 270 patients who received nivolumab 3 mg/kg administered intravenously over 60 minutes every 2 weeks with a minimum follow-up of 8.3 months were evaluable for efficacy. Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. The first tumour assessments were conducted 8 weeks after the start of treatment and continued every 8 weeks thereafter up to 48 weeks, then every 12 weeks until disease progression or treatment discontinuation, whichever occurred later. Tumour assessments were continued after treatment discontinuation in patients who discontinued treatment for reasons other than progression. Treatment beyond initial investigator-assessed RECIST, version 1.1-defined progression was permitted if the patient had a clinical benefit, did not have rapid disease progression, and was tolerating study drug as determined by the investigator. The primary efficacy outcome measure was ORR as determined by BICR. Additional efficacy measures included duration of response, PFS and OS.

The median age was 66 years (range: 38 to 90) with 55% ≥65 years of age and 14% ≥75 years of age. The majority of patients were white (86%) and male (78%). Baseline ECOG performance status was 0 (54%) or 1 (46%).

Table 26. Efficacy results (CA209275)^a:

⁺ denotes a censored observation
^a median follow-up 11.5 months.
^b Data unstable due to the limited duration of response.
^c included 4 drug-related deaths: 1 pneumonitis, 1 acute respiratory failure, 1 respiratory failure, and 1 cardiovascular failure.
NE: non-estimable

Results from post-hoc, exploratory analyses indicate that in patients with low (e.g. <1%) to no tumour PD-L1 expression, other patient characteristics (e.g. liver metastases, visceral metastases, baseline haemoglobin <10g/dL and ECOG performance status =1) might contribute to the clinical outcome.

Open-label phase ½ study (CA209032)

CA209032 was a Phase ½ open-label multi-cohort study which included a cohort of 78 patients (including 18 subjects who received planned crossover treatment with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg combination) with similar inclusion criteria to study CA209275 treated with nivolumab monotherapy 3 mg/kg for urothelial carcinoma. At a minimum follow-up of 9 months, investigator-assessed confirmed ORR was 24.4% (95% CI: 15.3, 35.4). The median duration of response was not reached (range: 4.4 – 16.6+ months). The median OS was 9.7 months (95% CI:7.26, 16.16) and the estimated OS rates were 69.2% (CI: 57.7, 78.2) at 6 months and 45.6% (CI: 34.2, 56.3) at 12 months.

Safety and efficacy in elderly patients

No overall differences in safety or efficacy were reported between elderly (≥65 years) and younger patients (<65 years). Data from SCCHN and adjuvant melanoma patients 75 years of age or older are too limited to draw conclusions on this population. Data from cHL patients 65 years of age or older are too limited to draw conclusions on this population.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with nivolumab in all subsets of the paediatric population in the treatment of malignant solid tumours, malignant neoplasms of lymphoid tissue and malignant neoplasms of the central nervous system (see section 4.2 for information on paediatric use).