In a normal immune response, the body can recognize the presence of tumors and mount a response to eradicate them. The process of eradicating a tumor begins with antigen-presenting cells that gather and process the antigens released by tumors. This activates the T-cells, which proliferate and attack the tumor.
Tumors have learned to evade the normal immune response by exploiting the immune checkpoint pathway. The Programmed Death Receptor-1 (PD-1) is a checkpoint protein expressed on the membrane of activated T-cells. The Programmed Death-Ligand 1 (PD-L1) and The Programmed Death-Ligand 2 (PD-L2) are checkpoint proteins expressed on tumor cells and tumor-infiltrating immune cells. When PD-L1 and PD-L2 attach to PD-1 receptors on the T-cells, the T-cells become inhibited and won't attack the tumor; thus, the tumor can continue to proliferate.
MERKEL CELL CARCINOMA (MCC)
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with an incidence of approximately 1,500 cases per year in the United States, with 12 percent of these cases presenting at stage 4. Merkel cell carcinoma has a high mortality rate, with a five-year survival of only 30-64 percent. Common sites of metastasis are the lymph nodes and distant skin sites.
On March 23, 2017, the US Food and Drug Administration (FDA) granted approval for avelumab (Bavencio®) for the treatment of adult and pediatric individuals 12 years and older with metastatic Merkel cell carcinoma (MCC). The safety and efficacy of avelumab (Bavencio®) was demonstrated in the JAVELIN Merkel 200 trial (NCT02155647), a phase 2, open-label, single-arm, multi-center study conducted in individuals with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease. The trial excluded individuals 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.
Study participants received avelumab (Bavencio®) 10 mg/kg as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity. Individuals 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 two weeks, and no need for salvage therapy, could continue treatment. Tumor response assessments were performed every six 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. To note, RECIST provides a standardized set of rules for response assessment using tumor shrinkage, based upon imaging modalities that are globally available and interpretable by most clinicians. This standardization, and the rules and criteria established, provide a framework for reproducible analysis and reporting of changes in tumor size. The reproducibility of these criteria and the correlations with historical trial results serve an important purpose in drug discovery. The efficacy analysis was conducted when the last patient enrolled had completed 12 months of follow-up.
A total of 88 individuals were enrolled. Baseline characteristics were a median age of 73 years (range: 33 to 88), and the ECOG performance score was 0 (56 percent) or 1 (44 percent). Seventy-five percent of individuals were 65 years or older, 35 percent were 75 or older, and 3 percent were 85 or older. Sixty-five percent of individuals were reported to have had one prior anti-cancer therapy for metastatic MCC and 35 percent had two or more prior therapies. Fifty-three percent of individuals had visceral metastases. All individuals had tumor samples evaluated for PD-L1 expression; of these, 66 percent were PD-L1-positive (≥ 1 percent of tumor cells), 18 percent were PD-L1 negative, and 16 percent 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 individuals with evaluable results, 52 percent had evidence of MCV.
The study showed an overall response rate (ORR) of 33 percent (95 percent confidence interval [CI]: 23.3–43.8 percent). Eleven percent of individuals experienced a complete response (95 percent CI: 6.6-19.9 percent) and 22 percent of individuals experienced a partial response (95 percent CI: 13.5-31.7 percent). Tumor responses were durable, with 86 percent of responses lasting for at least six months (n=25). Forty-five percent of responses lasted at least 12 months (n=13). Duration of response ranged from 2.8 to over 23.3 months.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
The urinary tract is composed of the the renal pelvis, ureters, bladder, and urethra. The innermost lining of the urinary tract is composed of urothelial cells. Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is the ninth most common cancer overall worldwide and it accounts for 90 percent of all bladder cancers. Squamous cell carcinoma comprises 1-7 percent of upper tract urothelial tumors. Adenocarcinoma accounts for less than 1 percent of upper tract tumors. Urothelial tumors of the renal pelvis and ureters are rare. Tumors of the renal pelvis account for approximately 5 percent of all urothelial tumors of the urinary tract.
On May 9, 2017, avelumab (Bavencio®) was approved by the US FDA for the treatment of individuals with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
The efficacy and safety of avelumab (Bavencio®) was demonstrated in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 individuals with locally advanced or metastatic 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. Individuals with active or history of central nervous system metastasis; other malignancies within the last five years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Individuals with autoimmune disease, other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Individuals were included regardless of their PD-L1 status.
Study participants received avelumab (Bavencio®) at a dose of 10 mg/kg intravenously every two weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every six 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 individuals 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 individuals with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), and 66 percent of individuals had an ECOG performance status 0 or 1. Forty-four percent of individuals had non-bladder urothelial carcinoma including 23 percent of individuals with upper tract disease, and 83 percent of individuals had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine individuals (4 percent) had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of individuals only received prior cisplatin-based regimens, 32 percent received only prior carboplatin-based regimens, and 20 percent received both cisplatin and carboplatin-based regimens. At baseline, 17 percent of individuals had a hemoglobin < 10 g/dL and 34 percent of individuals had liver metastases.
The median time to response was 2.0 months (range:1.3 to 11.0) among individuals followed for either > 13 weeks or > 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16 percent of individuals not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding individuals followed for > 13 weeks, 22 individuals (73 percent) had an ongoing response of six months or longer and 4 individuals (13 percent) had ongoing responses of 12 months or longer. Among the total 26 responding individuals followed for > 6 months, 22 individuals (85 percent) had ongoing responses of 6 months or longer and 4 individuals (15 percent) had ongoing responses of 12 months or longer.
For disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
RENAL CELL CARCINOMA (RCC)
In adults, renal cell carcinoma (RCC) accounts for 80-95 percent of all primary kidney cancers. When diagnosed, 65 percent of individuals have localized disease confined to the kidney. At 75-85 percent, the clear cell subtype of RCC accounts for the highest percentage among other subtypes of the disease.
The efficacy and safety of avelumab (Bavencio®) in combination with axitinib was demonstrated in the JAVELIN Renal 101 trial (NCT02684006), a phase 3, randomized, multicenter, open-label, study of avelumab (Bavencio®) in combination with axitinib in 886 individuals with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Individuals 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). Participants were randomized (1:1) to one of the following treatment arms:
Treatment with avelumab (Bavencio®) and axitinib continued until RECIST version 1.1 defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of avelumab (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.
- Avelumab (Bavencio®) 10 mg/kg intravenous infusion every two weeks in combination with axitinib 5 mg twice daily orally (N=442). Individuals who tolerated axitinib 5 mg twice daily without Grade 2 or greater axitinib-related adverse events for two 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 two weeks off (N=444) until radiographic or clinical progression or unacceptable toxicity.
Baseline characteristics were a median age of 61 years (range: 27 to 88), 38 percent of individuals were 65 years or older, and the ECOG PS was 0 (63 percent) or 1 (37 percent), respectively. Individual distribution by International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups was 21 percent favorable, 62 percent intermediate, and 16 percent 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 individuals with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥ 1 percent). Since PFS was statistically significant in individuals with PD-L1-positive tumors [HR 0.61 (95 percent CI: 0.48, 0.79)], it was then tested in the ITT population and a statistically significant improvement in PFS in the ITT population was also demonstrated.
Among individuals with previously untreated advanced RCC, treatment with avelumab (Bavencio®) plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.