Appeal type: Experimental/Investigational
Decision: Upheld

Diagnosis: Malignant peripheral nerve sheath tumor
Treatment: Ibrance 125mg OR CAPS, pre-service
The insurer denied the Ibrance 125mg OR CAPS, pre-service.
The denial is upheld.

The patient is a male with metastatic peripheral nerve sheath tumor. His provider has requested therapy with Ibrance based on NGS (next generation sequencing) panel testing.

No, the health plan should not cover the requested Ibrance.

No, the requested Ibrance is not more beneficial.

The use of NGS panel testing as a means to select anti-cancer therapy in advanced cancer remains an area of active research with ongoing studies of TPUR and MATCH. The concept of this approach is that all cancers are unique and each cancer has a specific individual molecular driver which can be identified using this testing. Once identified, specific therapy can be given to the patient directly treating their tumor. The majority of studies of this approach are fraught with methodological design issues such as lack of randomization and inclusion of large numbers of patients with established molecular drivers (i.e. [that is], breast cancer with ER [estrogen receptor] and HER2 [human epidermal growth factor receptor 2]) and then claiming that the identification and targeting of said known drivers contributes to benefit. There has been only one well designed trial of this approach, SHIVA, which demonstrated that this testing approach does not improve clinical outcomes for patients with advanced cancer.

Although Frampton, G.M., et al noted with the use of this assay across the broad spectrum of cancer cell line types resulted in "clinically actionable alterations" in 76% (percent) of tumors, at the moment there are no prospective or controlled trials showing that the use of this information to direct therapy improves health outcomes for patients with the diagnosis of cancer. In fact, the SHIVA study showed that the use of broad molecular mutation testing to direct therapy resulted in no improvement in progression free survival and the conclusion was that, "off label use of molecularly targeted agent should be discouraged."

Per Le Tourneau, C., et al, "The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy."

Per Singh, et al, "Overall, our study provides a real-world experience of the impact of CGP [comprehensive genomic profiling] in a community-based academic NCI [National Cancer Institute]-designated cancer center serving a highly diverse patient population, where molecular testing is based on a two-tier testing algorithm. While recognizing that a 10% overall rate of management change that is based on CGP is very modest, its use in certain subsets, such as advanced NSCLC [non-small cell lung cancer], where the impact currently is most significant appears to be justifiable and it has been found to be cost effective. In addition, we have identified multiple reasons for the relatively smaller clinical impact of CGP in other tumor types, despite a much larger proportion of patients with actionable genomic alterations reported. The impact however is anticipated to be increasing in light of new advances, e.g. [for example], recent studies do suggest expanding impact in breast (PI3kinase inhibitors) and pancreatic malignancies (poly ADP [adenosine diphosphate] ribose polymerase [PARP] inhibition). Although issues, such as optimal timing, access to clinical trials, and consolidating genomic testing need to be addressed at an institutional level, reports from testing platforms need to be carefully interpreted and ideally discussed in molecular tumor boards to provide the best treatment option possible. More prospective trials are needed that would better inform our choices for personalized treatment by providing assessments of overall survival and quality of life with choosing targeted therapies that are based on CGP when compared to conventional therapies."

In their appeal letter, the patient's provider writes, "Ibrance is an FDA [United States Food and Drug Administration] approved medication typically indicated as first line therapy for patients with hormone receptor positive, human epidermal growth factor receptor 2 negative advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant.  That being said, it is a targeted therapy known as a CDK 4/6 inhibitor [cyclin-dependent kinase 4 and 6]. It is not a traditional chemotherapy. Taken in combination with certain hormonal therapies, Ibrance works to put the brakes on cell growth in both healthy and cancer cells. This helps slow the progression of cancer." This is true, however this patient has malignant peripheral nerve sheath tumor (MPNST), not breast cancer, and so this is immaterial.

The provider further writes, "Please note treatment with Ibrance (palbociclib), is medically necessary, as treatment of this very rare cancer does not follow specific NCCN [National Comprehensive Cancer Network] guidelines. It does, however, require a combined modality approach and Ibrance is mentioned in the NCCN guidelines as being useful in certain circumstances." However, this patient has a soft tissue sarcoma, and this is addressed by the NCCN. The NCCN supports Ibrancee to treat liposarcoma, not other histologies such as MPNST.

Additionally, the provider writes, "We believe this patient has exhausted all proposed formulary alternatives and they are not viable options. The additional convenience of taking an oral tablet instead of injection/intravenous therapy will prevent [the patient] from having to come into the clinic and put himself at risk of infection during an ongoing pandemic." However, there are multiple NCCN options available to treat soft tissue sarcoma that can be used.

At this time, there is no published evidence to support the use of Ibrance in the treatment of peripheral nerve sheath tumor. Pre-clinical studies are not acceptable evidence of efficacy. This is classified as a type of soft tissue sarcoma, for which NCCN guidelines do exist. The NCCN only supports Ibrance to treat de-differentiated liposarcoma and does not support the use of this agent for other sarcoma histologies, or the use of this agent based on NGS panel testing. While approved in breast cancer, this is immaterial to a proposed use in sarcoma. There are multiple standard options available that can be used.