Bavencio

BAVENCIO is a programmed death ligand-1 (PD-L1) blocking antibody indicated for:

• Adults and pediatric patients 12 years and older with metastatic MCC. (
  1.1 Metastatic Merkel Cell Carcinoma

  BAVENCIO (avelumab) is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC)

  [see Clinical Studies (14.1)]

  .
  ,
  14.1 Metastatic Merkel Cell Carcinoma

  The efficacy and safety of BAVENCIO was demonstrated in the JAVELIN Merkel 200 trial (NCT02155647), an open-label, single--arm, multi-center study conducted in patients with histologically confirmed metastatic MCC. This trial consisted of two parts; Part A enrolled patients with metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease, and Part B enrolled patients with metastatic MCC who were treatment-naïve. The trial excluded patients with autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; CNS metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score ≥ 2.

  Patients received BAVENCIO 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than 2 weeks, and no need for salvage therapy, could continue treatment. Tumor response assessments were performed every 6 weeks.

  The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review committee (IRC) and IRC-assessed duration of response.

  Previously-treated Merkel Cell Carcinoma

  A total of 88 patients were enrolled in Part A. Baseline patient characteristics were a median age of 73 years (range: 33 to 88), 74% of patients were male, 92% were White, and the ECOG performance score was 0 (56%) or 1 (44%). Seventy-five percent of patients were 65 years or older, 35% were 75 or older, and 3% were 85 or older. Sixty-five percent of patients were reported to have had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies. Fifty-three percent of patients had visceral metastases. Sixty-six percent were PD-L1-positive (≥ 1% of tumor cells), 18% were PD-L1 negative, and 16% had non-evaluable results by an investigational immunohistochemistry assay. Archival tumor samples were evaluated for Merkel cell polyomavirus (MCV) using an investigational assay; of the 77 patients with evaluable results, 52% had evidence of MCV.

  Efficacy results are summarized in Table 10. Responses were observed in patients regardless of tumor PD-L1 expression or presence of MCV.

  Table 10: Efficacy Results from the JAVELIN Merkel 200 Trial in Previously-Treated Patients with Metastatic MCC (Part A)

  Efficacy Endpoints	BAVENCIO (N=88)
  CI: Confidence interval.
  Overall Response Rate (ORR)
  Overall response rate, n (%)	29 (33%)
  (95% CI)	(23, 44)
  Complete responses, n (%)	10 (11%)
  Partial responses, n (%)	19 (22%)
  Duration of Response (DOR)	N=29
  Median DOR in months (range)	40.5 (2.8, 41.5+)
  Patients with DOR ≥ 6 months, n (%)	26 (90%)
  Patients with DOR ≥ 12 months, n (%)	19 (66%)

  Treatment-naïve Merkel Cell Carcinoma

  A total of 116 patients were enrolled in Part B. Baseline patient characteristics were median age of 74 years (range: 41 to 93); 70% of patients were male; 65% were White, 31% were unknown or not collected, 2.6% were Asian, and 1.7% were Black; ECOG performance score was 0 (62%) or 1 (38%). Eighteen percent of patients were PD-L1-positive (≥ 1% of tumor cells), 75% were PD-L1-negative, and 7% had non-evaluable results by an investigational immunohistochemistry assay. Sixty percent of patients had Merkel cell polyomavirus (MCV).

  Efficacy results are presented in Table 11. Responses were observed in patients regardless of tumor PD-L1 expression or presence of MCV.

  Table 11: Efficacy Results of the JAVELIN Merkel 200 Trial in Patients with Treatment-Naïve Metastatic MCC (Part B)

  Efficacy Endpoints	BAVENCIO (N=116)
  CI: Confidence interval.
  Overall Response Rate (ORR)
  Overall response rate, n (%)	46 (40%)
  (95% CI)	(31, 49)
  Complete responses, n (%)	19 (16%)
  Partial responses, n (%)	27 (23%)
  Duration of Response (DOR)	N=46
  Median DOR in months, (range)	18.2 (1.2+, 28.3+)
  Patients with DOR ≥ 6 months, n (%)	35 (76%)
  Patients with DOR ≥ 12 months, n (%)	24 (52%)
  )

• Maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy. (
  1.2 Locally Advanced or Metastatic Urothelial Carcinoma

  First-Line Maintenance Treatment of Urothelial Carcinoma

  BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy

  [see Clinical Studies (14.2)]

  .

  Previously-treated Urothelial Carcinoma

  BAVENCIO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:

  • Have disease progression during or following platinum-containing chemotherapy
  • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
    [see Clinical Studies (14.2)].
  ,
  14.2 Locally Advanced or Metastatic Urothelial Carcinoma

  First-Line Maintenance Treatment of Urothelial Carcinoma

  The efficacy and safety of BAVENCIO was demonstrated in the JAVELIN Bladder 100 trial (NCT02603432), a randomized, multi-center, open-label study conducted in 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma that did not progress with first-line platinum-containing chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded.

  Randomization was stratified by best response to chemotherapy (CR/PR vs. stable disease [SD]) and site of metastasis (visceral vs. non-visceral) at the time of initiating first-line chemotherapy. Patients were randomized (1:1) to receive either BAVENCIO 10 mg/kg intravenous infusion every 2 weeks plus best supportive care (BSC) or BSC alone. Treatment was initiated within 4-10 weeks after the last dose of chemotherapy.

  Treatment with BAVENCIO continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of BAVENCIO was permitted beyond RECIST-defined disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, 8 weeks after randomization, then every 8 weeks up to 12 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression based on BICR assessment per RECIST v1.1.

  Baseline characteristics were well-balanced between arms. Overall, the median age was 69 years (range: 32 to 90), with 66% of patients ≥ 65 years of age and 24% of patients ≥ 75 years of age. Most patients were male (77%). The majority of patients were White (67%) and 22% were Asian. Baseline ECOG PS was 0 (61%) or 1 (39%).

  Fifty-six percent (56%) of patients received prior gemcitabine plus cisplatin, 38% of patients received prior gemcitabine plus carboplatin, and 6% of patients received prior gemcitabine plus cisplatin and gemcitabine plus carboplatin. Best response to first-line chemotherapy was CR or PR (72%) or SD (28%). Sites of metastasis prior to chemotherapy were visceral (55%) or non-visceral (45%). Fifty-one (51%) of patients had PD-L1-positive-tumors, 39% of patients had PD-L1-negative tumors, and 10% of patients had unknown PD-L1 tumor status. Six percent (6%) of patients received another PD-1/PD-L1 checkpoint inhibitor after discontinuation of treatment in the BAVENCIO plus BSC arm and 44% of patients in the BSC arm.

  The major efficacy outcome measure was overall survival (OS) in all randomized patients and patients with PD-L1-positive tumors. The results from a pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to BAVENCIO plus BSC as compared with BSC alone. An updated OS analysis was conducted when 452 deaths were observed. Consistent results were observed across the pre-specified subgroups of CR/PR versus SD to first-line chemotherapy.

  Table 12: Efficacy Results from the JAVELIN Bladder 100 Trial

  Efficacy Endpoints	BAVENCIO plus BSC	BSC
  	(N=350)	(N=350)
  BSC: Best supportive care; CI: Confidence interval; OS: overall survival.
  Primary OS
  Events (%)	145 (41.4)	179 (51.1)
  Median in months	21.4	14.3
  (95% CI)	(18.9, 26.1)	(12.9, 17.9)
  Hazard ratio (95% CI)	0.69 (0.56, 0.86)
  p-valuep-value based on 2-sided stratified log-rank.	0.001
  Updated OS
  Events (%)	215 (61.4)	237 (67.7)
  Median in months	23.8	15.0
  (95% CI)	(19.9, 28.8)	(13.5, 18.2)
  Hazard ratio (95% CI)	0.76 (0.63, 0.92)

  Figure 1: K-M Estimates for Updated OS from the JAVELIN Bladder 100 Trial

  

  In the pre-specified endpoint of OS among patients with PD-L1-positive tumors (n=358, 51%), the hazard ratio was 0.69 (95% CI: 0.52, 0.90) in the updated OS analysis for patients randomized to BAVENCIO plus BSC versus BSC alone. In an exploratory analysis of patients with PD-L1-negative tumors (n=270, 39%), the updated OS hazard ratio was 0.82 (95% CI: 0.62, 1.09).

  Previously-treated Urothelial Carcinoma

  The efficacy and safety of BAVENCIO was demonstrated in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 patients with locally advanced or metastatic urothelial carcinoma (UC) with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients with active or history of central nervous system metastasis; other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Patients with autoimmune disease, other than type I diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status.

  Patients received BAVENCIO at a dose of 10 mg/kg intravenously every 2 weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.

  Baseline demographic and disease characteristics for the 226 patients with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), 72% male, 80% White, and 34% and 66% of patients had an ECOG performance status 0 and 1, respectively. Forty-four percent of patients had non-bladder urothelial carcinoma including 23% of patients with upper tract disease, and 83% of patients had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine (4%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens. At baseline, 17% of patients had a hemoglobin < 10 g/dL and 34% of patients had liver metastases.

  Efficacy results are presented in Table 13. The median time to response was 2.0 months (range: 1.3 to 11.0) among patients followed for either ≥ 13 weeks or ≥ 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16% of patients not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding patients followed for ≥ 13 weeks, 22 patients (73%) had an ongoing response of 6 months or longer and 4 patients (13%) had ongoing responses of 12 months or longer. Among the total 26 responding patients followed for ≥ 6 months, 22 patients (85%) had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 12 months or longer.

  Table 13: Efficacy Results of the UC Cohorts in the JAVELIN Solid Tumor Trial

  Efficacy Endpoints	≥ 13 Weeks Follow-Up (N=226)	≥ 6 Months Follow-Up (N=161)
  CI: Confidence interval; NE: Not estimable; + denotes a censored value.
  Confirmed Overall Response Rate (ORR)
  Overall Response Rate n (%)	30 (13.3%)	26 (16.1%)
  (95% CI)	(9.1, 18.4)	(10.8, 22.8)
  Complete Response (CR) n (%)	9 (4.0%)	9 (5.6%)
  Partial Response (PR) n (%)	21 (9.3%)	17 (10.6%)
  Duration of Response (DOR)
  Median, months (range)	NE (1.4+ to 17.4+)	NE (1.4+ to 17.4+)

  Figure 1

  )
• Patients with locally advanced or metastatic UC who:
  • Have disease progression during or following platinum-containing chemotherapy. (
    1.2 Locally Advanced or Metastatic Urothelial Carcinoma

    First-Line Maintenance Treatment of Urothelial Carcinoma

    BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy

    [see Clinical Studies (14.2)]

    .

    Previously-treated Urothelial Carcinoma

    BAVENCIO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:

    • Have disease progression during or following platinum-containing chemotherapy
    • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
      [see Clinical Studies (14.2)].
    ,
    14.2 Locally Advanced or Metastatic Urothelial Carcinoma

    First-Line Maintenance Treatment of Urothelial Carcinoma

    The efficacy and safety of BAVENCIO was demonstrated in the JAVELIN Bladder 100 trial (NCT02603432), a randomized, multi-center, open-label study conducted in 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma that did not progress with first-line platinum-containing chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded.

    Randomization was stratified by best response to chemotherapy (CR/PR vs. stable disease [SD]) and site of metastasis (visceral vs. non-visceral) at the time of initiating first-line chemotherapy. Patients were randomized (1:1) to receive either BAVENCIO 10 mg/kg intravenous infusion every 2 weeks plus best supportive care (BSC) or BSC alone. Treatment was initiated within 4-10 weeks after the last dose of chemotherapy.

    Treatment with BAVENCIO continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of BAVENCIO was permitted beyond RECIST-defined disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, 8 weeks after randomization, then every 8 weeks up to 12 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression based on BICR assessment per RECIST v1.1.

    Baseline characteristics were well-balanced between arms. Overall, the median age was 69 years (range: 32 to 90), with 66% of patients ≥ 65 years of age and 24% of patients ≥ 75 years of age. Most patients were male (77%). The majority of patients were White (67%) and 22% were Asian. Baseline ECOG PS was 0 (61%) or 1 (39%).

    Fifty-six percent (56%) of patients received prior gemcitabine plus cisplatin, 38% of patients received prior gemcitabine plus carboplatin, and 6% of patients received prior gemcitabine plus cisplatin and gemcitabine plus carboplatin. Best response to first-line chemotherapy was CR or PR (72%) or SD (28%). Sites of metastasis prior to chemotherapy were visceral (55%) or non-visceral (45%). Fifty-one (51%) of patients had PD-L1-positive-tumors, 39% of patients had PD-L1-negative tumors, and 10% of patients had unknown PD-L1 tumor status. Six percent (6%) of patients received another PD-1/PD-L1 checkpoint inhibitor after discontinuation of treatment in the BAVENCIO plus BSC arm and 44% of patients in the BSC arm.

    The major efficacy outcome measure was overall survival (OS) in all randomized patients and patients with PD-L1-positive tumors. The results from a pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to BAVENCIO plus BSC as compared with BSC alone. An updated OS analysis was conducted when 452 deaths were observed. Consistent results were observed across the pre-specified subgroups of CR/PR versus SD to first-line chemotherapy.

    Table 12: Efficacy Results from the JAVELIN Bladder 100 Trial

    Efficacy Endpoints	BAVENCIO plus BSC	BSC
    	(N=350)	(N=350)
    BSC: Best supportive care; CI: Confidence interval; OS: overall survival.
    Primary OS
    Events (%)	145 (41.4)	179 (51.1)
    Median in months	21.4	14.3
    (95% CI)	(18.9, 26.1)	(12.9, 17.9)
    Hazard ratio (95% CI)	0.69 (0.56, 0.86)
    p-valuep-value based on 2-sided stratified log-rank.	0.001
    Updated OS
    Events (%)	215 (61.4)	237 (67.7)
    Median in months	23.8	15.0
    (95% CI)	(19.9, 28.8)	(13.5, 18.2)
    Hazard ratio (95% CI)	0.76 (0.63, 0.92)

    Figure 1: K-M Estimates for Updated OS from the JAVELIN Bladder 100 Trial

    

    In the pre-specified endpoint of OS among patients with PD-L1-positive tumors (n=358, 51%), the hazard ratio was 0.69 (95% CI: 0.52, 0.90) in the updated OS analysis for patients randomized to BAVENCIO plus BSC versus BSC alone. In an exploratory analysis of patients with PD-L1-negative tumors (n=270, 39%), the updated OS hazard ratio was 0.82 (95% CI: 0.62, 1.09).

    Previously-treated Urothelial Carcinoma

    The efficacy and safety of BAVENCIO was demonstrated in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 patients with locally advanced or metastatic urothelial carcinoma (UC) with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients with active or history of central nervous system metastasis; other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Patients with autoimmune disease, other than type I diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status.

    Patients received BAVENCIO at a dose of 10 mg/kg intravenously every 2 weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.

    Baseline demographic and disease characteristics for the 226 patients with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), 72% male, 80% White, and 34% and 66% of patients had an ECOG performance status 0 and 1, respectively. Forty-four percent of patients had non-bladder urothelial carcinoma including 23% of patients with upper tract disease, and 83% of patients had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine (4%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens. At baseline, 17% of patients had a hemoglobin < 10 g/dL and 34% of patients had liver metastases.

    Efficacy results are presented in Table 13. The median time to response was 2.0 months (range: 1.3 to 11.0) among patients followed for either ≥ 13 weeks or ≥ 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16% of patients not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding patients followed for ≥ 13 weeks, 22 patients (73%) had an ongoing response of 6 months or longer and 4 patients (13%) had ongoing responses of 12 months or longer. Among the total 26 responding patients followed for ≥ 6 months, 22 patients (85%) had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 12 months or longer.

    Table 13: Efficacy Results of the UC Cohorts in the JAVELIN Solid Tumor Trial

    Efficacy Endpoints	≥ 13 Weeks Follow-Up (N=226)	≥ 6 Months Follow-Up (N=161)
    CI: Confidence interval; NE: Not estimable; + denotes a censored value.
    Confirmed Overall Response Rate (ORR)
    Overall Response Rate n (%)	30 (13.3%)	26 (16.1%)
    (95% CI)	(9.1, 18.4)	(10.8, 22.8)
    Complete Response (CR) n (%)	9 (4.0%)	9 (5.6%)
    Partial Response (PR) n (%)	21 (9.3%)	17 (10.6%)
    Duration of Response (DOR)
    Median, months (range)	NE (1.4+ to 17.4+)	NE (1.4+ to 17.4+)

    Figure 1

    )
  • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (
    1.2 Locally Advanced or Metastatic Urothelial Carcinoma

    First-Line Maintenance Treatment of Urothelial Carcinoma

    BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy

    [see Clinical Studies (14.2)]

    .

    Previously-treated Urothelial Carcinoma

    BAVENCIO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:

    • Have disease progression during or following platinum-containing chemotherapy
    • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
      [see Clinical Studies (14.2)].
    ,
    14.2 Locally Advanced or Metastatic Urothelial Carcinoma

    First-Line Maintenance Treatment of Urothelial Carcinoma

    The efficacy and safety of BAVENCIO was demonstrated in the JAVELIN Bladder 100 trial (NCT02603432), a randomized, multi-center, open-label study conducted in 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma that did not progress with first-line platinum-containing chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded.

    Randomization was stratified by best response to chemotherapy (CR/PR vs. stable disease [SD]) and site of metastasis (visceral vs. non-visceral) at the time of initiating first-line chemotherapy. Patients were randomized (1:1) to receive either BAVENCIO 10 mg/kg intravenous infusion every 2 weeks plus best supportive care (BSC) or BSC alone. Treatment was initiated within 4-10 weeks after the last dose of chemotherapy.

    Treatment with BAVENCIO continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of BAVENCIO was permitted beyond RECIST-defined disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, 8 weeks after randomization, then every 8 weeks up to 12 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression based on BICR assessment per RECIST v1.1.

    Baseline characteristics were well-balanced between arms. Overall, the median age was 69 years (range: 32 to 90), with 66% of patients ≥ 65 years of age and 24% of patients ≥ 75 years of age. Most patients were male (77%). The majority of patients were White (67%) and 22% were Asian. Baseline ECOG PS was 0 (61%) or 1 (39%).

    Fifty-six percent (56%) of patients received prior gemcitabine plus cisplatin, 38% of patients received prior gemcitabine plus carboplatin, and 6% of patients received prior gemcitabine plus cisplatin and gemcitabine plus carboplatin. Best response to first-line chemotherapy was CR or PR (72%) or SD (28%). Sites of metastasis prior to chemotherapy were visceral (55%) or non-visceral (45%). Fifty-one (51%) of patients had PD-L1-positive-tumors, 39% of patients had PD-L1-negative tumors, and 10% of patients had unknown PD-L1 tumor status. Six percent (6%) of patients received another PD-1/PD-L1 checkpoint inhibitor after discontinuation of treatment in the BAVENCIO plus BSC arm and 44% of patients in the BSC arm.

    The major efficacy outcome measure was overall survival (OS) in all randomized patients and patients with PD-L1-positive tumors. The results from a pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to BAVENCIO plus BSC as compared with BSC alone. An updated OS analysis was conducted when 452 deaths were observed. Consistent results were observed across the pre-specified subgroups of CR/PR versus SD to first-line chemotherapy.

    Table 12: Efficacy Results from the JAVELIN Bladder 100 Trial

    Efficacy Endpoints	BAVENCIO plus BSC	BSC
    	(N=350)	(N=350)
    BSC: Best supportive care; CI: Confidence interval; OS: overall survival.
    Primary OS
    Events (%)	145 (41.4)	179 (51.1)
    Median in months	21.4	14.3
    (95% CI)	(18.9, 26.1)	(12.9, 17.9)
    Hazard ratio (95% CI)	0.69 (0.56, 0.86)
    p-valuep-value based on 2-sided stratified log-rank.	0.001
    Updated OS
    Events (%)	215 (61.4)	237 (67.7)
    Median in months	23.8	15.0
    (95% CI)	(19.9, 28.8)	(13.5, 18.2)
    Hazard ratio (95% CI)	0.76 (0.63, 0.92)

    Figure 1: K-M Estimates for Updated OS from the JAVELIN Bladder 100 Trial

    

    In the pre-specified endpoint of OS among patients with PD-L1-positive tumors (n=358, 51%), the hazard ratio was 0.69 (95% CI: 0.52, 0.90) in the updated OS analysis for patients randomized to BAVENCIO plus BSC versus BSC alone. In an exploratory analysis of patients with PD-L1-negative tumors (n=270, 39%), the updated OS hazard ratio was 0.82 (95% CI: 0.62, 1.09).

    Previously-treated Urothelial Carcinoma

    The efficacy and safety of BAVENCIO was demonstrated in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 patients with locally advanced or metastatic urothelial carcinoma (UC) with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients with active or history of central nervous system metastasis; other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Patients with autoimmune disease, other than type I diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status.

    Patients received BAVENCIO at a dose of 10 mg/kg intravenously every 2 weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.

    Baseline demographic and disease characteristics for the 226 patients with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), 72% male, 80% White, and 34% and 66% of patients had an ECOG performance status 0 and 1, respectively. Forty-four percent of patients had non-bladder urothelial carcinoma including 23% of patients with upper tract disease, and 83% of patients had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine (4%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens. At baseline, 17% of patients had a hemoglobin < 10 g/dL and 34% of patients had liver metastases.

    Efficacy results are presented in Table 13. The median time to response was 2.0 months (range: 1.3 to 11.0) among patients followed for either ≥ 13 weeks or ≥ 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16% of patients not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding patients followed for ≥ 13 weeks, 22 patients (73%) had an ongoing response of 6 months or longer and 4 patients (13%) had ongoing responses of 12 months or longer. Among the total 26 responding patients followed for ≥ 6 months, 22 patients (85%) had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 12 months or longer.

    Table 13: Efficacy Results of the UC Cohorts in the JAVELIN Solid Tumor Trial

    Efficacy Endpoints	≥ 13 Weeks Follow-Up (N=226)	≥ 6 Months Follow-Up (N=161)
    CI: Confidence interval; NE: Not estimable; + denotes a censored value.
    Confirmed Overall Response Rate (ORR)
    Overall Response Rate n (%)	30 (13.3%)	26 (16.1%)
    (95% CI)	(9.1, 18.4)	(10.8, 22.8)
    Complete Response (CR) n (%)	9 (4.0%)	9 (5.6%)
    Partial Response (PR) n (%)	21 (9.3%)	17 (10.6%)
    Duration of Response (DOR)
    Median, months (range)	NE (1.4+ to 17.4+)	NE (1.4+ to 17.4+)

    Figure 1

    )

• First-line treatment, in combination with axitinib, of patients with advanced RCC. (
  1.3 Advanced Renal Cell Carcinoma

  BAVENCIO in combination with axitinib is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC)

  [see Clinical Studies (14.3)]

  .
  ,
  14.3 Advanced Renal Cell Carcinoma

  The efficacy and safety of BAVENCIO in combination with axitinib was demonstrated in the JAVELIN Renal 101 trial (NCT02684006), a randomized, multicenter, open-label, study of BAVENCIO in combination with axitinib in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Patients with autoimmune disease or conditions requiring systemic immunosuppression were excluded.

  Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest of the world). Patients were randomized (1:1) to one of the following treatment arms:

  • BAVENCIO 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily orally (N=442). Patients who tolerated axitinib 5 mg twice daily without Grade 2 or greater axitinib-related adverse events for 2 consecutive weeks could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
  • Sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off (N=444) until radiographic or clinical progression or unacceptable toxicity.

  Treatment with BAVENCIO and axitinib continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration BAVENCIO and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at 6 weeks, then every 6 weeks thereafter up to 18 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression by BICR.

  Baseline characteristics were a median age of 61 years (range: 27 to 88); 38% of patients were 65 years or older; 75% were male; 75% were White, 15% Asian, 2% Black, 1% American Indian or Alaskan Native, 7% unknown; 4% were Hispanic or Latino; ECOG PS was 0 (63%) or 1 (37%); and 63% of patients were PD-L1 positive, 28% were PD-L1 negative, and 8% had unknown PD-L1 status. Patient distribution by International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups was 21% favorable, 62% intermediate, and 16% poor.

  The major efficacy outcome measures were progression-free survival (PFS), as assessed by an BICR using RECIST v1.1 and overall survival (OS) in patients with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥ 1%). PFS was statistically significant in patients with PD-L1-positive tumors [HR 0.61 (95% CI: 0.48, 0.79)] and in the ITT population. The final analysis for OS was not statistically significant for either the PD-L1-positive or ITT population.

  Efficacy results for the ITT population are presented in Table 14 and Figure 2.

  Table 14: Efficacy Results from JAVELIN Renal 101 Trial - ITT

  Efficacy Endpoints	BAVENCIO plus Axitinib (N=442)	Sunitinib (N=444)
  BICR: Blinded Independent Central Review; CI: Confidence interval; NE: Not estimable; NS: not statistically significant.
  Progression-Free Survival (PFS)Based on BICR assessment.
  Events (%)	180 (41)	216 (49)
  Median in months (95% CI)	13.8 (11.1, NE)	8.4 (6.9, 11.1)
  Hazard ratio (95% CI)	0.69 (0.56, 0.84)
  p-valuep-value based on 2-sided stratified log-rank.	0.0002
  Overall Survival (OS)
  Events (%)	283 (64)	295 (66)
  Median in months (95% CI)	44.8 (39.7, 51.1)	38.9 (31.4, 45.2)
  Hazard ratio (95% CI)	0.88 (0.75, 1.04)
  p-value	NS
  Confirmed Objective Response Rate (ORR)
  Objective Response Rate n (%)	227 (51.4)	114 (25.7)
  (95% CI)	(46.6, 56.1)	(21.7, 30.0)
  Complete Response (CR) n (%)	15 (3.4)	8 (1.8)
  Partial Response (PR) n (%)	212 (48)	106 (24)

  Figure 2: K-M Estimates for PFS based on BICR Assessment – ITT

  

  Figure 2

  )

• Premedicate for the first 4 infusions and subsequently as needed. (
  2.1 Premedication

  Premedicate patients with an antihistamine and with acetaminophen prior to the first 4 infusions of BAVENCIO. Premedication should be administered for subsequent BAVENCIO doses based upon clinical judgment and presence/severity of prior infusion reactions

  [see Dosage and Administration (2.5)and Warnings and Precautions (5.2)].
  )
• Merkel Cell Carcinoma
  : 800 mg every 2 weeks. (
  2.2 Recommended Dosage for MCC

  The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
  )
• Urothelial Carcinoma
  ; 800 mg every 2 weeks. (
  2.3 Recommended Dosage for UC

  The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
  )
• Renal Cell Carcinoma
  : 800 mg every 2 weeks in combination with axitinib 5 mg orally twice daily. (
  2.4 Recommended Dosage for RCC

  The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.

  When axitinib is used in combination with BAVENCIO, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of two weeks or longer. Review the Full Prescribing Information for axitinib prior to initiation.
  )

Administer BAVENCIO as an intravenous infusion over 60 minutes.

Injection: 200 mg/10 mL (20 mg/mL), clear, colorless to slightly yellow solution in a single-dose vial.

• Immune-Mediated Adverse Reactions
  (
  5.1 Severe and Fatal Immune-Mediated Adverse Reactions

  BAVENCIO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

  Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

  Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

  Withhold or permanently discontinue BAVENCIO depending on severity

  [see Dosage and Administration (2.5)].

  In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

  Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

  Immune-Mediated Pneumonitis

  BAVENCIO can cause immune-mediated pneumonitis. Immune-mediated pneumonitis occurred in 1.1% (21/1854) of patients receiving BAVENCIO, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%) and Grade 2 (0.6%) adverse reactions. Pneumonitis led to permanent discontinuation of BAVENCIO in 0.3% and withholding of BAVENCIO in 0.3% of patients.

  Systemic corticosteroids were required in all (21/21) patients with pneumonitis. Pneumonitis resolved in 57% (12/21) of the patients. Of the 5 patients in whom BAVENCIO was withheld for pneumonitis, 5 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of pneumonitis.

  With other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

  Immune-Mediated Colitis

  BAVENCIO can cause immune-mediated colitis. The primary component of the immune-mediated colitis consisted of diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

  Immune-mediated colitis occurred in 1.5% (27/1854) of patients receiving BAVENCIO, including Grade 3 (0.4%) and Grade 2 (0.8%) adverse reactions. Colitis led to permanent discontinuation of BAVENCIO in 0.5% and withholding of BAVENCIO in 0.4% of patients.

  Systemic corticosteroids were required in all (27/27) patients with colitis. Colitis resolved in 70% (19/27) of the patients. Of the 8 patients in whom BAVENCIO was withheld for colitis, 5 reinitiated treatment with BAVENCIO after symptom improvement; of these, 40% had recurrence of colitis.

  Hepatotoxicity and Immune-Mediated Hepatitis

  BAVENCIO as a single agent

  BAVENCIO can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.1% (20/1854) of patients receiving BAVENCIO, including fatal (0.1%), Grade 3 (0.8%), and Grade 2 (0.2%) adverse reactions. Hepatitis led to permanent discontinuation of BAVENCIO in 0.6% and withholding of BAVENCIO in 0.2% of patients.

  Systemic corticosteroids were required in all (20/20) patients with hepatitis. Hepatitis resolved in 60% (12/20) of the patients. Of the 4 patients in whom BAVENCIO was withheld for hepatitis, 4 reinitiated treatment with BAVENCIO after symptom improvement; of these, 25% had recurrence of hepatitis.

  BAVENCIO with Axitinib

  BAVENCIO in combination with axitinib can cause hepatotoxicity with higher-than-expected frequencies of Grade 3 and 4 ALT and AST elevation compared to BAVENCIO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. For elevated liver enzymes, interrupt BAVENCIO and axitinib and consider administering corticosteroids as needed

  [see Dosage and Administration (2.5)].

  In patients treated with BAVENCIO in combination with axitinib in the advanced RCC trials, increased ALT and increased AST were reported in 9% (Grade 3) and 7% (Grade 4) of patients. In patients with ALT ≥ 3 times ULN (Grades 2-4, n=82), ALT resolved to Grades 0-1 in 92%. Among the 73 patients who were rechallenged with either BAVENCIO (n=3) or axitinib (n=25) administered as a single agent or with both (n=45), recurrence of ALT ≥3 times ULN was observed in no patient receiving BAVENCIO, 6 patients receiving axitinib, and 15 patients receiving both BAVENCIO and axitinib

  .

  Twenty-two (88%) patients with a recurrence of ALT ≥3 ULN subsequently recovered to Grade 0-1 from the event. Immune-mediated hepatitis was reported in 7% of patients, including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Hepatotoxicity led to permanent discontinuation in 6.5% and immune-mediated hepatitis led to permanent discontinuation of either BAVENCIO or axitinib in 5.3% of patients. Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidal immunosuppressant. Resolution of hepatitis occurred in 31 of the 35 patients at the time of data cut-off.

  Immune-Mediated Endocrinopathies

  Adrenal Insufficiency

  BAVENCIO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Withhold BAVENCIO depending on severity

  [see Dosage and Administration (2.5)]

  .

  Immune-mediated adrenal insufficiency occurred in 0.6% (11/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%), and Grade 2 (0.4%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of BAVENCIO in 0.1% and withholding of BAVENCIO in 0.1% of patients.

  Systemic corticosteroids were required in all (11/11) patients with adrenal insufficiency. Adrenal insufficiency resolved in 18% (2/11) of patients. Of the 2 patients in whom BAVENCIO was withheld for adrenal insufficiency, none reinitiated treatment with BAVENCIO.

  Hypophysitis

  BAVENCIO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated. Withhold or permanently discontinue BAVENCIO depending on severity

  [see Dosage and Administration (2.5)]

  .

  Immune-mediated pituitary disorders occurred in 0.1% (1/1854) of patients receiving BAVENCIO which was a Grade 2 (0.1%) adverse reactions. Hypopituitarism did not lead to withholding of BAVENCIO in this patient. Systemic corticosteroids were not required in this patient.

  Thyroid Disorders

  BAVENCIO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated. Withhold or permanently discontinue BAVENCIO depending on severity

  [see Dosage and Administration (2.5)]

  .

  Thyroiditis

  occurred in 0.2% (4/1854) of patients receiving BAVENCIO, including Grade 2 (0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation or withholding of BAVENCIO in any patients. No patients with thyroiditis required systemic corticosteroids. Thyroiditis did not resolve in any patients (0/4).

  Hyperthyroidism

  occurred in 0.4% (8/1854) of patients receiving BAVENCIO, including Grade 2 (0.3%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of BAVENCIO in any patients and led to withholding of BAVENCIO in 0.1% of patients. Systemic corticosteroids were required in 25% (2/8) of patients with hyperthyroidism. Hyperthyroidism resolved in 88% (7/8) of the patients. Of the 2 patients in whom BAVENCIO was withheld for hyperthyroidism, 2 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of hyperthyroidism.

  Hypothyroidism

  occurred in 5% (97/1854) of patients receiving BAVENCIO, including Grade 3 (0.2%) and Grade 2 (3.6%) adverse reactions. Hypothyroidism led to permanent discontinuation of BAVENCIO in 0.1% and withholding of BAVENCIO in 0.4% of patients. Systemic corticosteroids were required in 6% (6/97) of patients with hypothyroidism. Hypothyroidism resolved in 6% (6/97) of the patients. Of the 8 patients in whom BAVENCIO was withheld for hypothyroidism, none reinitiated BAVENCIO.

  Type I Diabetes Mellitus, which can present with Diabetic Ketoacidosis:

  Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO depending on severity

  [see Dosage and Administration (2.5)]

  .

  Immune-mediated Type I diabetes mellitus occurred in 0.2% (3/1854) of patients receiving BAVENCIO, including Grade 3 (0.2%) adverse reactions. Type I diabetes mellitus led to permanent discontinuation of BAVENCIO in 0.1% of patients. Type I diabetes mellitus did not lead to withholding of BAVENCIO in any patient. Systemic corticosteroids were not required in any patient with Type I diabetes mellitus. Type I diabetes mellitus resolved in no patient and all patients required ongoing insulin treatment.

  Immune-Mediated Nephritis with Renal Dysfunction

  BAVENCIO can cause immune-mediated nephritis.

  Immune-mediated nephritis with renal dysfunction occurred in 0.1% (2/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%) and Grade 2 (0.1%) adverse reactions. Nephritis with renal dysfunction led to permanent discontinuation of BAVENCIO in 0.1% of patients. Nephritis did not lead to withholding of BAVENCIO in any patient.

  Systemic corticosteroids were required in 100% of patients with nephritis with renal dysfunction. Nephritis with renal dysfunction resolved in 50% of the patients.

  Immune-Mediated Dermatologic Adverse Reactions

  BAVENCIO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue BAVENCIO depending on severity

  [see Dosage and Administration (2.5)]

  .

  Immune-mediated dermatologic adverse reactions occurred in 6% (108/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%) and Grade 2 (1.9%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of BAVENCIO in 0.3% of patients and withholding of BAVENCIO in 0.4% of patients.

  Systemic corticosteroids were required in 25% (27/108) of patients with dermatologic adverse reactions. One patient required the addition of tacrolimus to high-dose corticosteroids.

  Dermatologic adverse reactions resolved in 46% (50/108) of the patients. Of the 8 patients in whom BAVENCIO was withheld for dermatologic adverse reactions, 4 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of dermatologic adverse reaction.

  Other Immune-Mediated Adverse Reactions

  The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% (unless otherwise noted) in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies

  .

  Severe or fatal cases have been reported for some of these adverse reactions.

  Cardiac/Vascular:

  Myocarditis, pericarditis

  ,

  vasculitis.

  Gastrointestinal:

  Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis.

  Nervous System:

  Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

  Ocular:

  Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

  Musculoskeletal and Connective Tissue:

  Myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica.

  Endocrine:

  Hypoparathyroidism.

  Other (Hematologic/Immune):

  Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.
  )
  • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and may result in solid organ transplant rejection.
  • Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
  • Withhold or permanently discontinue based on severity and type of reaction.
• Infusion-related reactions
  : Interrupt, slow the rate of infusion, or permanently discontinue BAVENCIO based on severity of reaction. (
  5.2 Infusion-Related Reactions

  BAVENCIO can cause severe or life-threatening infusion-related reactions

  [see Adverse Reactions (6.1)]

  . Premedicate with antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions

  [see Dosage and Administration (2.5)and Adverse Reactions (6.1)]

  .

  Infusion-related reactions occurred in 26% of patients treated with BAVENCIO including 3 (0.2%) Grade 4 and 10 (0.5%) Grade 3 infusion-related reactions. Ninety-three percent of patients received premedication with antihistamine and acetaminophen. Eleven (85%) of the 13 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids. Fifteen percent of patients had infusion-related reactions that occurred after the BAVENCIO infusion was completed.
  )
• Complications of allogeneic HSCT
  : Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (
  5.3 Complications of Allogeneic HSCT

  Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

  Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.
  )
• Major adverse cardiovascular events
  : Optimize management of cardiovascular risk factors. Discontinue BAVENCIO in combination with axitinib for Grade 3-4 events. (
  5.4 Major Adverse Cardiovascular Events (MACE)

  BAVENCIO in combination with axitinib can cause severe and fatal cardiovascular events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events.

  MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib in a randomized trial, JAVELIN Renal 101. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%). Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months).
  )
• Embryo-fetal toxicity
  : BAVENCIO can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (
  5.5 Embryo-Fetal Toxicity

  Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking BAVENCIO, inform the patient of the potential risk to a fetus. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least one month after the last dose of BAVENCIO

  [see Use in Specific Populations (8.1, 8.3)]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of BAVENCIO in pregnant women

  [see Clinical Pharmacology (12.1)]

  . Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death

  [see Data]

  . Human IgG1 immunoglobulins (IgG1) are known to cross the placenta. Therefore, BAVENCIO has the potential to be transmitted from the mother to the developing fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  Animal reproduction studies have not been conducted with BAVENCIO to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering BAVENCIO during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to BAVENCIO may increase the risk of developing immune-mediated disorders or altering the normal immune response.
  ,
  8.3 Females and Males of Reproductive Potential

  Contraception

  Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  . Advise females of reproductive potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO.
  )