Clinical UM Guideline

 

Subject: Olaratumab (Lartruvo™)
Guideline #: CG-DRUG-102 Publish Date:    06/28/2018
Status: New Last Review Date:    05/03/2018

Description

This document addresses olaratumab (Lartruvo) (Eli Lilly and Company, Indianapolis, IN), a recombinant human immunoglobulin G subclass 1 (IgG1) monoclonal antibody used for the treatment of adults with late stage soft tissue sarcoma under certain conditions. Olaratumab specifically binds platelet-derived growth factor receptor α (PDGFRα), thereby blocking platelet derived growth factor-AA (PDGF-AA), PDGF-BB, and PDGF-CC binding and receptor activation.

Clinical Indications

Medically Necessary:

  1. Olaratumab is considered medically necessary when the following criteria are met:
    1. Individual has a histologically confirmed diagnosis of late stage soft tissue sarcoma (locally advanced or metastatic) not previously treated with an anthracycline; and
    2. Radiotherapy or surgery is not a curative treatment option; and
    3. Individual’s current Eastern Cooperative Oncology Group (ECOG) performance status is 0-2; and
    4. If the individual is less than 18 years of age, olaratumab is not used as first-line chemotherapy; and
    5. Olaratumab is used in combination with doxorubicin and, after at least 8 cycles with doxorubicin or earlier discontinuation of doxorubicin due to toxicity, and then if so chosen, continuing olaratumab as monotherapy in the absence of unacceptable toxicities until disease progression.

Not Medically Necessary:

Olaratumab is considered not medically necessary when the medically necessary criteria are not met and for all other indications.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J9285

Injection, olaratumab, 10 mg [Lartruvo]

 

 

 

ICD-10 Diagnosis

 

 

C47.0-C47.9

Malignant neoplasm of peripheral nerves and autonomic nervous system

 

C48.0-C48.8

Malignant neoplasm of retroperitoneum and peritoneum

 

C49.0-C49.9

Malignant neoplasm of other connective and soft tissue [excluding GIST]

 

Discussion/General Information

Sarcomas are a diverse group of rare solid tumors of mesenchymal cell origin with distinct clinical and pathologic features, usually divided into two broad categories:

Collectively, sarcomas account for approximately 1% of all adult malignancies and 15% of pediatric malignancies. In 2018, the American Cancer Society estimates that about 13,000 people will be diagnosed with soft tissue sarcoma in the United States and approximately 5000 deaths will occur as a result of the disease. More than 50 different histologic subtypes of soft tissue sarcoma have been identified; the most common are undifferentiated pleomorphic sarcoma, gastrointestinal stromal tumors (GISTs), liposarcoma, leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors (MPNSTs). Metastasis most commonly occurs in the lungs; liver and peritoneum. Rhabdomyosarcoma is the most common soft tissue sarcoma of children and adolescents.

Surgical resection is the standard primary treatment for most individuals with soft tissue sarcoma. Radiation therapy with or without chemotherapy may be used prior to surgery to downstage large high-grade tumors to enable effective surgical resection. Radiation therapy may also be administered either as primary, preoperative, or postoperative treatment. For individuals with advanced, unresectable, or metastatic disease, chemotherapy with single agents or combination regimens have typically been used.

Historically, little progress has been made in improving the median overall survival (OS) of individuals with advanced soft-tissue sarcoma. Standard treatment has consisted of regimens of doxorubicin alone or doxorubicin in combination with ifosfamide. The prognosis for those with metastatic disease has been poor because of the limited efficacy of traditional regimens.

On October 19, 2016 the U.S. Food and Drug Administration (FDA) granted accelerated approval of olaratumab (Lartruvo), in combination with doxorubicin, for the treatment of adults with soft tissue sarcoma with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. (Lartruvo Prescribing Information, 2017).

The National Comprehensive Cancer Network (NCCN) clinical practice guideline on soft tissue sarcoma (2018) recommends olaratumab and doxorubicin as one of several recommended combination treatment options for soft tissue sarcoma subtypes with non-specific histologies.

The primary published study in support of olaratumab use for soft tissue sarcoma was an open-label phase 1b and randomized phase 2 study of doxorubicin plus olaratumab for the treatment of unresectable or metastatic soft-tissue sarcoma published by Tap and colleagues in 2016. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival (PFS). For both the phase 1b and phase 2 parts of the study, eligible subjects were at least 18 years of age or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and available tumor tissue to determine PDGFRα expression by immunohistochemistry. In the phase Ib study, 15 subjects were treated with olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m2) on day 1 of each 21-day cycle up to a maximum of eight cycles. After eight cycles of the combination drug therapy, in the absence of unacceptable toxicities or disease progression subjects were given olaratumab monotherapy until disease progressed.

The FDA approval of olaratumab (Lartruvo) was based on the phase 2 part of the study in which 133 subjects were randomized in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m²) or doxorubicin alone (75 mg/m²) on day 1 of each 21-day cycle for up to eight cycles. After completion of eight cycles of doxorubicin, individuals in the olaratumab plus doxorubicin group could receive olaratumab monotherapy until disease progression and those is the doxorubicin group could receive olaratumab monotherapy after documented disease progression. A total of 129 subjects (97%) received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival (PFS) in phase 2 was 6.6 months with olaratumab plus doxorubicin and 4.1 months with doxorubicin. Median OS was 26.5 months with olaratumab plus doxorubicin and 14.7 months with doxorubicin. The objective response rate was 18.2% with olaratumab plus doxorubicin and 11.9% with doxorubicin. Steady state olaratumab serum concentrations were reached during the third cycle. Results were not separately reported for the doxorubicin group that received olaratumab monotherapy after documented disease progression. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: 8 [13%] of 64 subjects vs doxorubicin: 9 [14%] of 65 subjects).

Two other clinical trials involving olaratumab have been published (Chiorean, 2014 and Doi, 2014). Both were small phase 1 studies that evaluated the safety and acceptable dosing of olaratumab for future clinical trials. The Chiorean trial consisted of 19 subjects with advanced solid tumors divided across five cohorts. The authors indicated that olaratumab was well tolerated and showed preliminary antitumor activity at the recommended phase II doses of 16 mg/kg weekly and 20 mg/kg biweekly. The Doi trial consisted of 16 Japanese subjects with advanced/refractory solid malignancies divided across three cohorts. No dose-limiting toxicities occurred; therefore, the maximum tolerated dose was not reached. The authors reported that olaratumab had an acceptable safety profile. Additionally noted was that single and multiple doses of olaratumab at 15 mg⁄ kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg⁄ kg every 2 weeks (cohort 2) could represent an acceptable schedule for future trials.

A randomized, double-blind, placebo-controlled, phase III trial of doxorubicin plus olaratumab vs doxorubicin plus placebo in individuals with advanced or metastatic soft tissue sarcoma is currently ongoing (ANNOUNCE trial; NCT02451943). It was designed to evaluate the effectiveness of olaratumab across multiple subtypes of soft tissue sarcoma and the estimated date of study completion is January 2020.

Other Proposed Uses

Additional uses of olaratumab under investigation include glioblastoma, non-small cell lung cancer, prostate cancer and ovarian cancer.  However, at this time there is insufficient published evidence to support the use of olaratumab for any indication other than for the treatment of late stage soft tissue sarcoma when specific criteria are met.  A 2017 study by Gerber and colleagues in 131 individuals with NSCLC did not find that the addition of olaratumab to a treatment regimen of paclitaxel/carboplatin significantly improved OS or PFS.

Definitions

ECOG Performance Status: A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale:

Metastatic: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Monoclonal antibody: A laboratory-produced substance that can locate and bind to specific cells wherever they are in the body. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to their target cell.

Overall-survival (OS): The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that individuals diagnosed with the disease remain alive.

Progression-free survival (PFS): The length of time during and after treatment that an individual lives but does not get worse (usually measured by the size of a tumor or amount of cancer in the body).

References

Peer Reviewed Publications:

  1. Chiorean EG, Sweeney C, Youssoufian H, et al. A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014; 73(3):595-604.
  2. Doi T, Ma Y, Dontabhaktuni A, et al. Phase I study of olaratumab in Japanese patients with advanced solid tumors. Cancer Sci. 2014; 105(7):862-869.
  3. Gerber DE, Swanson P, Lopez-Chavez A, et al. Phase II study of olaratumab with paclitaxel/carboplatin (P/C) or P/C alone in previously untreated advanced NSCLC. Lung Cancer. 2017. 111:108-115.
  4. Sheng JY, Movva S. Systemic therapy for advanced soft tissue sarcoma. Surg Clin North Am. 2016; 96(5):1141-1156.
  5. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016; 388(10043):488-497.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Lartruvo [Product Information], Indianapolis, IN. Eli Lilly and Co., February 2017. Available at: http://pi.lilly.com/us/lartruvo-uspi.pdf. Accessed on March 26, 2018.
  2. National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology. For additional information visit the NCCN website: http://www.nccn.org. Accessed on  March 26, 2018.
    • Soft Tissue Sarcoma (V.1.2018). Revised October 21, 2017.
  3. National Institute of Health. A randomized, double-blind, placebo-controlled, phase 3 trial of doxorubicin plus olaratumab versus doxorubicin plus placebo in patients with advanced or metastatic soft tissue sarcoma. Clinical trials.gov Identifier: NCT02451943. Last updated on August 28, 2017. Available at: https://clinicaltrials.gov/ct2/show/record/NCT02451943?term=NCT02451943&rank=1. Accessed on March 26, 2018.
Websites for Additional Information
  1. American Cancer Society. Sarcoma, adult soft tissue cancer. Last revised January 4, 2018. Available at: https://www.cancer.org/cancer/soft-tissue-sarcoma/about.html. Accessed on March 26, 2018.
Index

IMC-3G3
LY3012207
Lartruvo
Olaratumab

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

05/03/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

05/02/2018

Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.00097 Olaratumab (Lartruvo™) to new clinical utilization management guideline document with the same title. Updated Discussion/General Information and References sections.