March 2017, Vol 10, Eighth Annual Payers' Guide - Drug Updates, Online First
Lisa A. Raedler, PhD, RPh
Medical Writer

Urothelial carcinoma (also known as transitional-cell carcinoma) is the most common subtype of bladder cancer, accounting for more than 90% of bladder cancer diagnoses in the United States.1 In 2016, nearly 77,000 cases of bladder cancer are expected to be diagnosed in the United States, and more than 16,000 people will die from this disease.2 The incidence of bladder cancer increases with age, with a median age of 73 years at diagnosis.2

Bladder cancer is more common in men than in women and is the fourth most common cancer in men, after prostate, lung, and colorectal cancer.2 Although not common in women, those diagnosed with bladder cancer have a worse prognosis than men.3

Overall, the prognosis associated with bladder cancer is favorable for patients with localized disease: the 5-year relative survival rate is 70%, which decreases to 5% for patients with distant disease.2

High recurrence rates, intensive surveillance strategies, and expensive treatments for bladder cancer significantly contribute to medical costs for this disease.4 In 2010, bladder cancer was the ninth most costly cancer in the United States, with cumulative costs of $4 billion.5

Treatment of locally advanced and metastatic bladder cancer has remained unchanged for the past several decades. Platinum-based and gemcitabine-containing chemotherapy regimens are used for the initial treatment of advanced-stage disease, and no specific agent or regimen is considered standard therapy in the relapsed setting.6-8 For patients with relapsed bladder cancer, the current National Comprehensive Cancer Network guidelines prioritize participation in clinical trials.6

Data show that several types of solid tumors are vulnerable to checkpoint inhibition, including bladder cancer.9,10 The immune system recognizes foreign proteins (antigens) as abnormal and destroys them, while protecting “self”-tissue. Immune checkpoints, including programmed-cell death (PD)-1 and PD ligand 1 (PD-L1), are pathways that are hardwired into the immune system to allow self-tolerance.9 By blocking these immune checkpoint pathways, novel immunooncology agents can strengthen the ability of tumor-infiltrating T-lymphocytes (T-cells) to recognize the danger associated with cancer cells and subsequently remove them.9

Atezolizumab Approved for Bladder Cancer

On May 18, 2016, the US Food and Drug Administration (FDA) approved ate­zolizumab (Tecentriq; Genentech), an intravenously administered PD-L1 inhibitor, for the treatment of patients with locally advanced or metastatic urothelial carcinoma that progressed during or after platinum-containing chemotherapy, or for patients whose disease progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.10,11

This approval of atezolizumab was based on the objective response rate (ORR) results from the single-arm, phase 2 clinical trial IMvigor 210 showing the ability of atezolizumab to shrink the tumor in a significant number of patients with this disease.10-12

Concurrently, the FDA approved the Ventana PD-L1 (SP142) assay, a complementary diagnostic test that detects the expression of PD-L1 levels on the tumor and on immune cells, which can help clinicians identify patients who would benefit most from atezolizumab therapy.10

Atezolizumab was approved under the FDA’s accelerated approval program, which allows faster approval of a drug to treat a serious or life-threatening disease based on clinical data demonstrating that the drug has an effect on a surrogate end point that is likely to predict clinical outcome.10

“Tecentriq provides these patients with a new therapy targeting the PD-L1 pathway. Products that block PD-1/PD-L1 interactions are part of an evolving story about the relationship between the body’s immune system and its interaction with cancer cells,”10 stated Richard Pazdur, MD, FDA’s Director of the Office of Hematology and Oncology Products.

Specialty Pharmacy Distribution

Atezolizumab is distributed through specific specialty pharmacies. Physicians’ offices and hospitals can access atezolizumab through several specialty pharmacies, including ASD Healthcare, BioSolutions Direct, Cardinal Health Specialty Distribution, Cura­Script Specialty Distribution, M&D Specialty Distribution, McKesson Specialty Health, McKesson Plasma and Biologics, Oncology Supply, Besse Medical, and Smith Medical Partners.13

Mechanism of Action

PD-L1 on tumor cells and tumor-infiltrating immune cells contribute to the inhibition of the body’s antitumor immune response in the tumor microenvironment.11 When PD-L1 binds to PD-1 and B7.1 receptors on T-cells and antigen-presenting cells, cytotoxic T-cell activity, T-cell proliferation, and cytokine production are suppressed.11

Atezolizumab is a monoclonal antibody that, when bound to PD-L1, blocks its interactions with PD-1 and B7.1 receptors and releases PD-L1– and PD-1–mediated inhibition of the body’s immune response.11

Dosing and Administration

In patients with locally advanced or metastatic urothelial carcinoma that progressed after a platinum-containing regimen, atezolizumab is administered intravenously, 1200 mg every 3 weeks, until disease progression or until unacceptable toxicity.11

The first infusion of atezolizumab should be administered for 60 minutes. If this infusion is well-tolerated, subsequent infusions can be delivered for 30 minutes. Atezolizumab should not be administered as an intravenous (IV) push or bolus.11

The IMvigor 210 Pivotal Clinical Trial

The efficacy of atezolizumab was established in the open-label, multicenter, phase 2 IMvigor 210 study.11,12 This study evaluated the safety and efficacy of atezolizumab in 310 patients with locally advanced or metastatic urothelial cancer that progressed during or after a platinum-containing chemotherapy regimen or within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant regimen.11,12

Patients’ PD-L1 expression status was assessed using the Ventana PD-L1 (SP142) assay at a central laboratory and categorized based on the percentage of PD-L1–positive immune cells in the tumor microenvironment. Overall, 32% of the 310 patients had PD-L1 expression of ≥5%, defined as PD-L1–stained tumor-infiltrating immune cells covering at least 5% of the tumor area.11 The remaining 68% of patients had PD-L1 expression <5%.11

Atezolizumab was administered intravenously at 1200 mg every 3 weeks until disease progression or until unacceptable toxicity.11 Tumor response assessments were performed every 9 weeks for the first year, followed by every 12 weeks. The key efficacy measures were ORR (assessed by an independent review facility using the Response Evaluation Criteria in Solid Tumors version 1.1) and the duration of response.11

After a median treatment duration of 14.4 months with atezolizumab, the ORR was 14.8% (95% confidence interval [CI], 11.1-19.3), including 5.5% complete responses (Table).11 The median duration of response has not been reached for the full patient population at the most recent analysis (range, approximately 2.1-13.8 months).11

Table

The ORR was 26% (95% CI, 17.7-35.7) in patients with PD-L1 expression ≥5% compared with 9.5% (95% CI, 5.9-14.3) in patients with PD-L1 expression <5%; the duration of response in the latter group was 12.7 months (Table).11

The ORR was 22% (95% CI, 12.3-34.7) among 59 patients whose disease progressed after neoadjuvant or adjuvant chemotherapy.11

Adverse Events

The safety of single-agent atezolizu­mab was based on data from 310 patients with urothelial carcinoma.11 The patients’ median age was 66 years, and the majority of these patients were white (91%) and male (78%).11

Overall, 41% of patients received at least 2 systemic regimens in the metastatic setting.11 The median duration of treatment with atezolizumab at the time of the data analysis was 12.3 weeks (range, 0.1-46 weeks).11

The most common (≥20% of patients) grade 1 or 2 adverse reactions in patients who received atezolizumab included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%).11 The most common (≥2% of patients) grade 3 or 4 adverse reactions in patients who received atezolizumab included nausea (2%), abdominal pain (4%), fatigue (6%), urinary tract infection (9%), back or neck pain (2%), hematuria (3%), and dyspnea (4%).

Serious adverse reactions occurred in 45% of patients who received atezoliz­umab.11 Overall, 3% of patients discontinued therapy because of adverse reactions, and treatment interruption was required in 27% of patients.11 The most common (>1% of patients) events resulting in the interruption of atezoliz­umab therapy were increases in liver enzyme levels, urinary tract infection, diarrhea, fatigue, confusion, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis.11

Atezolizumab has no contraindications.11

Warnings and Precautions

Immune-related pneumonitis
Patients taking atezolizumab should be assessed for the signs and symptoms of pneumonitis. Steroids should be administered for grade 2 or higher pneumonitis, followed by a taper. Atezolizumab should be withheld until resolution of grade 2 pneumonitis, and discontinued for grade 3 or 4 pneumonitis.11

Immune-related hepatitis
Patients should be assessed for elevations in alanine aminotransferase levels, aspartate aminotransferase levels, and total bilirubin levels. Steroids should be administered for grade 2 or higher hepatitis, followed by a taper. Atezolizumab should be withheld until the resolution of grade 2 hepatitis and discontinued for grade 3 or 4 immune-mediated hepatitis.11

Immune-related colitis
Atezolizumab should be withheld for grade 2 diarrhea or colitis. Steroids followed by a taper are warranted if symptoms persist for more than 5 days or if colitis recurs. Patients with grade 3 diarrhea or colitis should receive IV methylprednisolone, and atezolizumab should be withheld. Atezolizumab should be discontinued for grade 4 diarrhea or colitis.11

Immune-related endocrinopathies
Patients receiving atezolizumab had thyroid disorders, adrenal insufficiency, hypophysitis, and type 1 diabetes mellitus, including diabetic ketoacidosis; patients should be monitored for these complications.11

Infection
Infection was observed in 38.4% of patients with urothelial car­cinoma who received atezolizumab. Atezolizumab should be withheld for severe infections.11

Infusion-related reactions
Severe infusion reactions were noted in 1.3% of more than 1900 patients involved in clinical trials of atezolizumab. Infusion of atezolizumab should be interrupted or slowed in patients with mild or moderate reactions, and discontinued in patients with severe reactions.11

Use in Specific Populations

Atezolizumab therapy can cause fetal harm when administered to a pregnant woman. Women of reproductive age should use effective contraception during therapy and for 5 months after the last atezolizumab dose. Female fertility may be compromised with atezo­lizumab therapy.11

Women should not breastfeed with atezolizumab therapy, and for ≥5 months after the last atezolizumab dose.11

Atezolizumab has not been studied in children. No differences in the safety and effectiveness of atezolizumab were observed between patients aged ≥65 years and younger patients.11

No dosage adjustment is recommended for patients with renal impairment. Dosage adjustment is not necessary in patients with mild hepatic impairment. Atezolizumab has not been studied in patients with moderate or severe hepatic impairment.11

Conclusion

Atezolizumab is the first PD-L1 inhibitor approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial cancer that progressed after a platinum-containing regimen in the neoadjuvant, adjuvant, or advanced-disease setting. Atezolizumab demonstrated high response rates and durable responses, with a median duration of response not yet reached after approximately 14 months of follow-up.

As a result of atezolizumab’s distinct mechanism of action, combinations with standard or other novel agents may improve outcomes for patients with urothelial cancer. Researchers are currently evaluating the activity of atezo­lizumab monotherapy and atezolizu­mab-based combinations in patients with urothelial carcinoma, as well as in other solid and liquid tumors.14

Copyright © 2016 American Health & Drug Benefits. Reprinted with permission.  


 

References

  1. National Cancer Institute. Bladder cancer treatment—health professional version (PDQ). Updated February 18, 2016. www.cancer.gov/types/bladder/hp/bladder-treatment-pdq. Accessed July 7, 2016.
  2. National Cancer Institute. SEER Stat Fact Sheets: Bladder Cancer. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed July 7, 2016.
  3. American Cancer Society. Cancer Facts & Figures 2016. www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf. Accessed July 7, 2016.
  4. Svatek RS, Hollenbeck BK, Holmäng S, et al. The economics of bladder cancer: costs and considerations of caring for this disease. Eur Urol. 2014;66:253-262.
  5. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103:117-128.
  6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): bladder cancer. Version 2.2016. June 23, 2016. www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed July 7, 2016.
  7. Loehrer PJ, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10:1066-1073.
  8. Von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23:4602-4608.
  9. Tseng WW, Malu S, Zhang M, et al. Analysis of the intratumoral adaptive immune response in well differentiated and dedifferentiated retroperitoneal liposarcoma. Sarcoma. 2015;1:1-9.
  10. US Food and Drug Administration. FDA approves new, targeted treatment for bladder cancer. May 18, 2016. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm501762.htm. Accessed July 6, 2016.
  11. Tecentriq (atezolizumab) injection [prescribing information]. South San Francisco, CA: Genentech; May 2016.
  12. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920.
  13. Genentech Access Solutions. Tecentriq distribution. www.genentech-access.com/hcp/brands/tecentriq/learn-about-our-services/product-distribution.html. Accessed August 11, 2016.
  14. Clinicaltrials.gov. Atezolizumab. https://clinicaltrials.gov/ct2/results?term=atezolizumab&Search=Search. Accessed July 11, 2016.
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Last modified: May 8, 2017
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