Universal Genetic Testing Detects More Inherited Mutations Than Guideline Based Approach

SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, and germline testing of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics. Very few studies have compared the prevalence of germline findings in patients with cancer, not selected by practice guidelines, and the impact of universal testing strategy for inherited germline variants in patients with cancer has remained unclear. The purpose of this present study was to determine if universal genetic testing in patients with cancer identifies more inherited cancer predisposition variants than a guideline-based approach, and also find out if there is an association between universal genetic testing and clinical management.

The authors in this prospective, multicenter cohort study, assessed germline genetic alterations among patients with solid tumors, receiving care at Mayo Clinic Cancer Centers and Mayo Clinic Health System community oncology practice in the US, between April 2018, and March 2020, as a part of 2 year Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) program. Patients were NOT selected based on cancer type, stage of disease, family history of cancer, race/ethnicity, age at diagnosis, multifocal tumors, or personal history of multiple malignant neoplasms. Clinical, demographic, and family history data and pathologic information were collected on all patients from medical records or self-administered questionnaires.Single-Gene-versus-MultiGene-Testing

Germline sequencing using a Next-Generation Sequencing panel of 84 genes was offered at no cost, utilizing the Invitae Multi-Cancer Panel. Whole Genome Sequencing, deletion and duplication analysis, and variant interpretation were performed and Pathogenic Germline Variants (PGV) were classified as High (relative risk more than 4), Intermediate (relative risk, 2-4), or Low (relative risk less than 2) penetrance, or recessive medically actionable variants. Test results were disclosed to the patient, and those with Pathogenic Germline Variants (PGVs) were invited for genetic counseling.

The authors compared multi-gene panel testing with guideline-based testing, using guidelines from the National Comprehensive Cancer Network (NCCN) and the National Society of Genetic Counselors (NSGC) and the American College of Medical Genetics (ACMG), to determine whether genetic testing was indicated for a particular patient. For patients who met the guidelines, the only genes tested were those recommended by the tumor-specific guideline. This study included patients with a broad mix of cancer types at various stages. The final analytic cohort consisted of 2984 patients, out of the 3095 patients enrolled in the study. The mean patient age was 61 years, 53% were male and 44% of patients had Stage IV disease at the time of genomic analysis. A family history of cancer in a first-degree relative was reported in 34% of the participants. The goals of this study were to examine the proportion of Pathogenic Germline Variants (PGVs) detected with a universal testing strategy compared with a targeted testing strategy based on clinical guidelines, as well as uptake of cascade genetic testing in families, when offered at no cost.

It was noted that Pathogenic Germline Variants (inherited mutation in a gene) associated with the development of their cancer was found in 13.3% of patients, including moderate and high-penetrance cancer susceptibility genes. In this study, 1 in 8 patients had a PGV, half of which would not have been detected using a guideline-based testing approach. Of those with a high-penetrance PGVs, 28.2% had modifications in their treatment, based on the finding. About 6.4% had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. However, only 17.6% of participants with PGVs had family members undergoing no-cost cascade genetic testing when offered.

It was concluded that in this large, prospective, multicenter cohort study with a broad mixture of cancer types and stages, universal multigene panel testing was associated with increased detection of clinically actionable heritable variants, compared with a targeted testing strategy based on clinical guidelines. Approximately 30% of patients with high-penetrance variants had modifications in their treatment, suggesting that wider clinical implementation of universal genetic testing and acceptance in oncology practice, may be beneficial.

Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. Samadder NJ, Riegert-Johnson D, Boardman L, et al. JAMA Oncol. Published online October 30, 2020. doi:10.1001/jamaoncol.2020.6252

Single Agent Trilaciclib Prevents Multilineage Myelosuppression during Chemotherapy

SUMMARY: Chemotherapy remains one of the mainstays of cancer treatment. However, chemotherapy-induced damage of Hematopoietic Stem and Progenitor Cells (HSPC) causes multi-lineage myelosuppression. Currently, available therapies such as Granulocyte-Colony Stimulating Factors (G-CSF) and Erythropoiesis-Stimulating Agents (ESAs) prevent the myelosuppressive effects of chemotherapy in only one lineage. Therapeutic agents that lead to protection of multiple lineages simultaneously would be clinically meaningful.

Trilaciclib is a highly potent, selective, and reversible, intravenous, Cyclin-Dependent Kinase 4 and 6 (CDK 4/6) inhibitor, that transiently maintains G1 cell cycle arrest of Hematopoietic Stem and Progenitor Cells (HSPC), and protects them from damage by cytotoxic chemotherapy. Chemotherapy-induced damage of Hematopoietic Stem and Progenitor Cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib proactively preserves HSPC and immune system function during chemotherapy (myelopreservation). Preclinical studies have demonstrated that Trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery. Additionally, Trilaciclib enhances immune response, and preserves immune system function.

Small Cell Lung Cancer (SCLC) was chosen as the testing platform, to explore the potential myelopreservation benefit of Trilaciclib for the following reasons: 1) Cytotoxic chemotherapy for SCLC is notable for its myelotoxicity. 2) SCLC tumor cells replicate independent of CDK4/6, through the obligate loss of Retinoblastoma (RB1), allowing assessment of Trilaciclib’s effects on the host, without any potential direct effects on the tumor. 3) SCLC is a chemosensitive tumor, and provides an optimal setting to demonstrate that Trilaciclib does not antagonize chemotherapy efficacy.

The authors in this publication, pooled data from three randomized, double-blind, placebo-controlled Phase II trials, in patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC), to understand the effects of Trilaciclib on specific myelosuppression endpoints, with greater statistical precision. Individual results from these three randomized trials have previously been reported. In this pooled analysis, 123 patients received Trilaciclib along with chemotherapy (N=123), and 119 patients received Placebo along with chemotherapy (N=119). The median age in both treatment groups was 64 years. The objectives of this pooled data analysis was to summarize the utilization of G-CSFs, ESAs and RBC transfusions, and hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis, as well as explore the relationship between supportive care interventions and the myelopreservation benefits of Trilaciclib.

In the first study (NCT02499770), patients with newly diagnosed ES-SCLC received Trilaciclib 240 mg/m2 or Placebo IV, given daily on days 1 to 3, prior to chemotherapy, of each 21-day chemotherapy cycle with Etoposide and Carboplatin. In the second trial (NCT03041311), patients with newly diagnosed ES-SCLC received Trilaciclib 240 mg/m2 or Placebo IV, given daily on days 1 to 3, prior to chemotherapy, of each 21-day chemotherapy cycle with Etoposide, Carboplatin and Atezolizumab (TECENTRIQ®), followed by single-agent Atezolizumab alone, every 21 days. In the third study (NCT02514447), patients with previously treated ES-SCLC in the second or third line setting, received Trilaciclib 240 mg/m2 or Placebo IV daily, prior to Topotecan 1.5 mg/m2 IV given daily on days 1 to 5 of each 21-day cycle. The Primary outcome measures included percentage of patients with Severe (Grade 4) Neutropenia as well as duration of Severe Neutropenia. Supportive intervention endpoints included percentage of patients with RBC transfusions on or after week 5, and number of RBC transfusion events on or after week 5, as well as percentage of patients receiving ESAs. This study also explored the percentage of patients with hospitalizations due to Chemotherapy Induced Myelosuppression (neutropenia, anemia, thrombocytopenia) or sepsis, as well as incidence of hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis, per 100 cycles.

It was noted that fewer patients receiving Trilaciclib had Severe Neutropenia (11.4% versus 52.9%) or Grade 3/4 anemia (20.3% versus 31.9%), compared to Placebo, respectively, and the use of supportive care interventions such as G-CSF and ESAs was significantly reduced. Hospitalizations due to Chemotherapy Induced Myelosuppression or sepsis occurred in significantly fewer patients and significantly less often among patients receiving Trilaciclib prior to chemotherapy, compared to those who received Placebo. Trilaciclib reduced the percentage of patients with Severe Neutropenia and duration of Severe Neutropenia, regardless of G-CSF administration. The proportion of patients receiving RBC transfusions was consistently lower with each cycle, among patients receiving Trilaciclib, whereas RBC transfusions in the Placebo group almost doubled over time.

It was concluded that Trilaciclib prior to chemotherapy significantly and meaningfully reduced Chemotherapy Induced Myelosuppression and the need for supportive care interventions, for the management of Severe Neutropenia and Grade 3/4 anemia, in patients with ES-SCLC. Chemotherapy-induced Severe Neutropenia was reduced with Trilaciclib, irrespective of G-CSF administration.

Trilaciclib Reduces the Need for Growth Factors and Red Blood Cell Transfusions to Manage Chemotherapy-Induced Myelosuppression. Ferrarotto R, Anderson I, Medgyasszay B, et al. Presented at: IASLC 2020 North America Conference on Lung Cancer; October 16-17, 2020.

ASCO Guideline on Treatment of Metastatic Carcinoma and Myeloma of the Femur

SUMMARY: The American Society of Clinical Oncology on June 20, 2020, approved the first joint Musculoskeletal Tumor Society (MSTS)/American Society for Radiation Oncology (ASTRO)/ASCO guideline on the care of patients with metastatic carcinoma and myeloma of the femur. The skeleton is a frequent site of metastatic carcinoma and myeloma. Primary malignancies that commonly metastasize to bone include breast, lung, prostate, kidney, and thyroid. The incidence of bone metastases is approximately 70% in patients with breast or prostate cancer and 35% in patients with lung or kidney cancer, based on autopsy studies. The lifetime risk of developing multiple myeloma is 1 in 132, and 70-80% of patients present with osteolytic lesions in the skeleton. Malignant lesions involving the bone can be painful and can result in pathologic fractures, impairing functional capacity, quality of life and Overall Survival (OS). These patients may require radiation therapy, surgery or both. The National Institutes of Health estimated that for the years 2000-2004, the national economic burden of metastatic bone disease was 12.6 billion dollars, representing 17% of the total direct medical cost of oncology care. These costs would be significantly higher in 2020.

The following recommendations were prepared and endorsed by the Musculoskeletal Tumor Society (MSTS), American Society for Radiation Oncology (ASTRO), and American Society of Clinical Oncology (ASCO). The purpose of this Clinical Practice Guideline is to provide medical, radiation, and surgical providers with a practical set of recommendations, regarding the management of patients with metastatic or myelomatous lesions of the femur, based on a systematic review of published information and consensus expert opinion. These guideline recommendations are intended to guide medical oncologists, radiation oncologists, and primary care physicians in making timely referrals, and address three main therapeutic areas-the use of Bone Modifying Agents, radiation therapy, and surgery.

1) Imaging and Clinical Findings: A combination of imaging findings and lesion-related pain is predictive of risk of pathologic femur fracture. There is no reliable evidence to suggest that MRI is a strong predictor of femur fracture.

2) Efficacy of Bone Modifying Agents (BMAs): The use of BMAs may assist in reducing incidence of femur fractures in patients with metastatic carcinoma or multiple myeloma and bone lesions.

3) Dosage Response of BMAs: Clinicians should consider decreasing the frequency of Zoledronic acid dosing to 12 weeks (compared to the standard 4-week interval), as this is associated with non-inferior Skeletal Related Events outcomes and similar adverse event rates, in patients with metastatic carcinoma or multiple myeloma. Clinicians should consider long-term use of BMAs to reduce skeletal related events in patients with multiple myeloma.

4) BMAs for Various Diagnoses: BMAs should be considered in patients with metastatic carcinoma or multiple myeloma with bone lesions at risk for fracture, regardless of tumor histology.

5) Imaging Findings and Atypical Fractures: Imaging findings of lateral cortical thickening may be associated with increased atypical femur fracture risk.

6) Efficacy of Radiation Therapy: Clinicians should consider the use of radiation therapy to decrease the rate of femur fractures in patients with metastatic carcinoma or multiple myeloma lesions, considered at increased risk, based on the combination of imaging findings and lesion-related pain.

7) Radiation Therapy and Prophylactic Femur Stabilization: Clinicians may consider the use of radiation therapy in patients undergoing prophylactic femur stabilization to reduce pain, improve functional status, and reduce the need for further intervention.

8) Radiation Therapy after Resection and Reconstruction: Radiation therapy may be considered after resection and reconstruction to reduce pain, improve functional status, and reduce the need for further intervention in patients with residual tumor, or those at increased risk of tumor recurrence.

9) Multi-Fraction Radiation Treatment: Clinicians should consider the use of multi-fraction in lieu of single fraction radiation treatment to reduce the risk of fracture in patients with metastatic carcinoma in the femur.

10) Estimating Survival and Reconstruction Method: Surgeons should utilize a validated method of estimating survival of the patient in choosing the method of reconstruction. Longer survival estimates may justify more durable reconstruction methods such as arthroplasty, if clinically appropriate.

11) Long Stem Hemiarthroplasty: When treating a femoral neck fracture with hemiarthroplasty, use of a long stem can be associated with increased intra-operative and post-operative complications and should only be used in patients with additional lesions in the femur.

12) Cephalomedullary Nailing: There is no advantage to routine use of cephalomedullary nails for diaphyseal metastatic lesions, as there does not appear to be a high frequency of new femoral neck lesions following intramedullary nailing.

13) Arthroplasty: Clinicians may consider arthroplasty to improve patient function and decrease the need for post-operative radiation therapy in patients with pathologic fractures from metastatic carcinoma in the femur.

http://msts.org/view/download.php/education/mbd-cpg-amended. Accessed October 28, 2020.

Immune Checkpoint Inhibitors Associated with High Activity in MSI-H Cancers

SUMMARY: The DNA MisMatchRepair (MMR) system plays a crucial role in repairing DNA replication errors in normal and cancer cells. It is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and accumulation of mutations (hypermutation) and the generation of neoantigens, triggering an enhanced antitumor immune response.

MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system. Defective MMR can be a sporadic or heritable event. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of Tumor Infiltrating Lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with Immune Checkpoint Iinhibitors (ICIs). The positive outcomes following ICI treatment in MSI-H tumors may be related to the possible association with Programmed Death-Ligand 1 (PD-L1) expression and the high Tumor Mutational Burden (TMB) of these diseases.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.Testing-for-Micro-Satellite-Instability-and-MisMatch-Repair-Deficiency

MSI testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC).

The authors in this publication conducted a systematic review and meta-analysis which included a total of 14 published articles that evaluated ICIs in the treatment of advanced MSI-H tumors from inception to December 2019. These articles were identified by searching the PubMed, EMBASE, and Cochrane Library databases. Overall, 939 patients in the 14 studies were analyzed, and the purpose of this study was to determine the outcomes in patients with advanced, MSI-H cancers, following treatment with ICIs. The selected studies for analysis had prospectively accrued patients with advanced or metastatic MSI-H/dMMR cancers, regardless of line of therapy, and data was available for Overall Response Rate (ORR) and/or survival analysis (Overall Survival and/or Progression Free Survival).

The studies included use of either, Avelumab (BAVENCIO®), Pembrolizumab (KEYTRUDA®), Ipilimumab (YERVOY®), Nivolumab (OPDIVO®), Atezolizumab (TECENTRIQ®) or Durvalumab (IMFINZI®). This analysis included a range of tumor types, and the Primary outcome of interest was Overall Response Rate (ORR). Secondary end points were median Progression Free Survival (PFS), median Overall Survival (OS), pooled rate of patients alive at 1, 2 and 3 years, and pooled rate of patients that attained Disease Control Rate (DCR), which is the sum of Stable Disease rate and ORR.

The pooled ORR was 41.5%, the pooled DCR was 62.8%, the pooled median PFS was 4.3 months and the pooled median OS was 24 months. The pooled 1 and 2-year OS were 75.6% and 56.5% respectively. Since only one study provided 3-year OS data, a formal pooled analysis for 3 years was not possible. The ORR was similar according to histologic analysis with the higher values for Gastric cancer (61.2%) and the lowest ORR associated with Colorectal cancer (47.1%), Endometrial (36.1%), and other tumors (35.5%).

It was concluded from this meta-analysis that Immune Checkpoint Inhibitors were associated with high activity, independent of tumor type and drug used, and molecular biomarkers such as MisMatch Repair proteins may have a predictive value for the activity of immunotherapy.

Outcomes Following Immune Checkpoint Inhibitor Treatment of Patients With Microsatellite Instability-High Cancers. A Systematic Review and Meta-analysis. Petrelli F, Ghidini M, Ghidini A, et al. JAMA Oncol. 2020;6:1068-1071.

Minimal Residual Disease Testing in Multiple Myeloma: The Time has Arrived.

Special Written by Dr. Robert Rifkin, Rocky Mountain Cancer Center | Sponsored by Adaptive Biotechnologies

Rising Importance of MRD Testing in Multiple Myeloma

In the early 2000s, the average overall survival rate for patients with multiple myeloma (MM) was only 3 years.1 With the advent of new therapies over the last 5 years, many patients with MM can now expect to achieve clinical complete response (CR). However, while this trend is expected to continue, the majority of these patients who achieve CR will eventually relapse, suggesting that existing therapies are insufficient and more sensitive testing is necessary to identify potentially undetected malignant cells.2

Minimal residual disease (MRD) refers to the small number of cancer cells that can remain in a patient’s body during and after treatment and may eventually cause recurrence of the disease. MRD is commonly assessed in lymphoid malignancies such as B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). In the event of the persistence of malignant B cells, the possibility of recurrence is more likely.3 To address this, MRD testing is now being used to monitor the effectiveness of therapies as well as subsequent treatment decisions by identifying the presence of MRD over time.

The Application of Next-Generation Sequencing

MRD testing in lymphoid malignancies has become increasingly valuable in predicting patient outcomes. While next-generation flow cytometry has been used for MRD testing in B-ALL, and has been standardized for highly sensitive MRD measurements (e.g. 10-6), as reported by Theunissen and Colleagues, standard flow cytometry is limited to a level of detection of 1 malignant cell in 10,000 cells assessed (e.g. 10-4)4. In contrast, next-generation sequencing (NGS) has a level of sensitivity of up to 1 malignant cell in 1,000,000 cells assessed (e.g. 10-6). 5,6

In the era of NGS, it is now possible to assess MRD beyond the standard response criteria for assessment of treatment efficacy. In a review that evaluated the prognostic value of MRD, patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of initial treatment.7

The clonoSEQ® Assay, an in vitro diagnostic (IVD) test that uses multiplex PCR and NGS to identify and quantify disease-associated DNA sequence rearrangements (or clonotypes) of the IgH, IgK and IgL receptor genes, has been FDA-cleared to monitor MRD in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). The assay can accurately and precisely quantify MRD at the DNA-sequence level. According to a recent analysis, clonoSEQ maintains accurate reporting of disease burden down to one malignant cell in 1 million healthy cells provided sufficient sample input.5,6

Patient-specific clonal sequences are identified at the time of diagnosis or high disease burden and can be used as a marker for MRD. Oftentimes, at the conclusion of therapy, MRD measurements can also be used to firmly establish a diagnosis of a molecular complete remission. In order to do this with an NGS assay, it is important to remember to obtain a baseline fresh bone marrow sample at the time of diagnosis. This will facilitate the identification of a dominant clone. In the event such a sample is not available, it is possible to identify the clone utilizing archived or fixed tissue.

Incorporating MRD Testing in Clinical Practice Guidelines

The future of MRD testing in MM, as reviewed by Oliva and colleagues, is clear: MRD testing in MM will be increasingly important as we strive for a cure.8 The course of MM is highly variable, and the clinical behavior is equally diverse. For this reason, MRD testing has been incorporated into clinical practice guidelines as a Standard of Care, as evidenced by the NCCN’s recommendation to assess MRD after each stage of treatment: post-induction, post-high-dose therapy/ASCT, post-consolidation, post-maintenance. NCCN updated their guidelines recently to note that during upfront diagnosis you could consider “baseline clone identification and storage of aspirate samples for future MRD testing by NGS”.9

In short, MRD testing in lymphoid malignancies should be leveraged to track a patient’s disease over time. This approach may aid in key clinical decision-making throughout the course of treatment. For example, if MRD is present in a B-ALL patient, therapy with blinatumomab is suggested over other agents and is now part of guidelines. If MRD is negative, alternative maintenance with the POMP regimen is often employed. Similar guidelines for MM and CLL are on the therapeutic horizon, and I suspect will soon be incorporated into evidence-based guidelines.

As we enter the new area of targeted therapy and the development of novel agents for all the diseases, testing for MRD will become increasingly important. In order to maintain a state-of-the-art clinical practice, and to foster best clinical practice in patient care, it essential that every clinician and stakeholder in the patient’s journey become familiar with these new MRD technologies, and how to integrate them into his or her overall care plan in order to improve clinical outcomes.

Important information

clonoSEQ is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect measurable residual disease (MRD) in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). clonoSEQ is also available for use in other lymphoid cancers as a CLIA-validated laboratory developed test (LDT) service. For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit https://www.clonoseq.com/technical-summary/.

1) Landgren O, Iskander K. J Intern Med. 2017;281(4):365-382.
2) Munshi NC, Anderson KC. J Clin Oncol. 2013;31 (20):2523-2526.
3) Perrot A, Lauwers-Cances V, Corre J, et al. Blood. 2018;132(23):2456-2464.
4) Theunissen P, Mejstrikova E, et al. Blood. (2017) 129 (3): 347–357.
5) clonoSEQ®. [technical summary]. Seattle, WA: Adaptive Biotechnologies; 2020.
6) Ching T, Duncan ME, et al. BMC Cancer. 2020; 20: 612.
7) Rajkumar SV, Kumar S. Mayo Clin Proc. 2016 Jan;91(1):101-19.
8) Oliva S, D’Agostino M, et al. Front Oncol. 2020; 10: 1.
9) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.1.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed March September 22nd, 2020. To view the most recent and complete version of the guideline, go to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use of application and disclaims any responsibility for their application or use in any way.

The Transition to Biosimilars: Managing Payor Challenges

Written by Dr. Robert Rifkin | Sponsored by Mylan Pharmaceuticals

Biologic agents have long played a vital role in oncology. Not only does this class of agents represent the best of science, but it also accounts for a tremendous increase in spend of the healthcare dollar. As the field of biologic therapies advances, the biosimilarity exercise has become relevant. The premise of biosimilarity is to decrease healthcare costs and improve access to care.1

This premise was first established with the affordable care act in the Biologics Price Competition and Innovation Act (BCPIA).2 Since its inception, a new pathway for approval of biosimilars was tested and implemented. The 351 (K) regulatory pathway was first tested with biosimilar filgrastim (filgrastim–sndz), or Zarxio.3 Initially, upon product launch, a modest discount of 15% was employed. (15%) The uptake was slow; however, when the market adjusted and uptake accelerated, an approximate 30% discount was in play.

Several other biosimilars have now entered the supportive care space. Specifically, in the case of short acting filgrastim, there are now competitors Nivestym (Filgrastim-aafi) with several additional biosimilar filgrastims under development. Within the pegfilgrastim arena, the position of the originator, Neulasta, has now been challenged by 3 other long-acting filgrastims: Fulphila (pegfilgrastim-jmdb), Udenyca (pegfilgrastim-cbqv), and Ziextenzo (pegfilgrastim-bmez).4 These original, early supportive care biosimilars have helped to define the marketplace, test regulatory mechanisms, and dispel any myths regarding their adoption.4

Herceptin (trastuzumab) also faces competition as new biosimilars enter space. Multiple biosimilars have now launched in addition to the originator molecule, including: Herzuma (trastuzumab-pkrb), Kanjinti (trastuzumab-anns), Ogivri (trastuzumab-dkst), Ontruzant (trastuzumab-dttb), and Trazimera (trastuzumab-qyyp).5 For the trastuzumabs, the large number of biosimilar options provides both competition in the marketplace in addition to a potential new source of significant confusion with distribution, supply chain, and inventory management. It is relatively unlikely that any payor or formulary will carry all five biosimilar trastuzumabs currently available in addition to any other biosimilar options slated for release over the next year.

Additionally, the rituximab space has become increasingly complex. Beyond the originator molecule, we can now choice to use Truxima (ritiximab abbs), or Ruxience (rituximab-pvvr), and several more launches are anticipated. The space is further complicated by the availability of a subcutaneous form of Rituxan Hycela (rituximab/hyaluronidase human), the only biosimilar available in subcutaneous injection. Unsurprisingly, this has created some from payors as all labeled indications are not initially the same for each product. Moving forward, rituximab biosimilar labels will soon be equivalent, and competition will then drive the marketplace.

In the real world, there still exist very real barriers to adoption including a clinical, ease of use, and economic barriers. It is likely payors will interpose themselves into each one of these. Multiple biosimilars are now being approved for each originator molecule. This will ultimately result in a decline in cost. Payors and other stakeholders will then be faced with complicated decisions of maintaining the originator on the formulary, deleting it and placing a biosimilar in its place, or perhaps carrying two versions of the same molecule, with preference being given to one. Most likely, most formularies will carry originator in addition to one or more biosimilars concurrently depending on the provider and payer landscape. the originator and a preferred biosimilar concurrently.

Several articles have reviewed the concept of switching between the biosimilar and the originator, and to date no significant safety signals have arisen.6 The payor landscape is impacted by product availability and opportunities to switch. This demonstrated safety of switching has incrementally impacted the payor landscape. Pharmacy Benefit Managers (PBM) have also been interwoven into the payor conundrum, with discounts and rebates providing an additional layer of complexity.

Not only is the transition to biosimilars complicated for payors, but the transition must also include all stakeholders involved in the ultimate selection of a therapeutic biologic. Providers and patients need to be very well educated regarding the concept of biosimilarity. Other stakeholders, including pharmacists, advanced practice providers, nurses, and admixture technologists, must be thoroughly educated. The electronic health record also needs to be updated to reflect the increasing numbers of biosimilars now available – including the preferred therapeutic agents in each circumstance.

Payors and clinicians alike will need to develop biosimilar teams, drug contracting strategies with and without GPO’s, and a thorough evaluation of clinical economics for each biosimilar. Biosimilars will assume an increasingly important role in the delivery of cancer care and it is important to approach this from a patient journey point of view (Fig. 1).

Figure 1: Patient Journey7

By tracing this from beginning to end, a formula for success may be developed.

The combination of clinical confidence, patient confidence, and operational excellence will be required to be sure that we are prepared for biosimilars and ensure patient access. The patient’s journey is complicated and increasingly influenced by the payor and other stakeholders . Providers, consideration of the revenue cycle, RN educators, pharmacists, admixture technologists, and infusion RNs all must play together to ensure the success of biosimilars. In alignment with the patient journey, diagnosis and treatment selection will be accomplished by the provider. This will be followed by insurance authorization, treatment education, treatment scheduling, treatment admixture, and finally the delivery of the drug to the well-educated patient. There are many potentials for success as well as failure (Fig. 2).

Figure 2: Drug Preparedness – Success vs. Failure7

The cornerstone for all to succeed, as well as all of the affected stakeholders managing paired challenges, remains education. This cannot be overstated. Numerous websites have now appeared, both branded and unbranded, to help deliver biosimilar education. Such websites may be found at the FDA8 and the Center for Biosimilars.9

In conclusion, as all the stakeholders become thoroughly educated, the many challenges outlined above will continue to present themselves in real-time. The success and adoption of current and future biosimilars will continue to depend on the sound education of all stakeholders, including payors, in addition to improved cost savings and access. Biosimilar usage will be important to ensure long-term sustainability on the market, and as biosimilar uptake increases, healthcare cost reduction and improvements to care access may be achieved.


1. Pittman WL, Wern C, Glode AE. Review of Biosimilars and Their Potential Use in Oncology Treatment and Supportive Care in the United States.
2. https://www.fda.gov/media/78946/download
3. U.S. Food & Drug Administration. Zarxio (filgrastim-sndz) Approval Letter. Published online March 6, 2015. Accessed June 19, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000Approv.pdf
4. Rugo H, Rifkin RM, Deckerc P, Bair AH, Morgan G. Demystifying Biosimilars: Development, Regulation and Clinical Use. Future Oncology. 15(7):777-790, 2019
5. AmerisourceBergen. Approval and launch dates for US biosimilars. Published June 19, 2020. Accessed June 25, 2020. http://gabionline.net/Reports/Approval-and-launch-dates-for-US-biosimilars?ct=t%28GONL+V20F19-6%29&mc_cid=2821e641cc&mc_eid=%5BUNIQID%5D
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FDA Approves KEYTRUDA® for Tumor Mutational Burden-High Solid Tumors

SUMMARY: The FDA on June 16, 2020 granted accelerated approval to KEYTRUDA® (Pembrolizumab) for the treatment of adult and pediatric patients with unresectable or metastatic Tumor Mutational Burden-High (10 or more mutations/megabase) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. The FDA on the same day also approved the FoundationOne® CDx assay (Foundation Medicine, Inc.) as a companion diagnostic for KEYTRUDA®. KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1 monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the tumor-specific effector T cells.

Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High, and less than 10 mutations/Megabase, as Low. (A megabase is 1,000,000 DNA basepairs).

KEYNOTE-158 is a multicenter, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. The accelerated approval was based on data from a prospectively-planned, retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic solid tumors with TMB-H, who were enrolled in KEYNOTE-158 study. Patients received KEYTRUDA® 200 mg IV every 3 weeks until unacceptable toxicity or documented disease progression. In this study, 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients with sufficient tissue for testing. Of these 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB 10 mutations /Megabase or more. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. TMB status was assessed using the FoundationOne® CDx assay. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety.

In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. After a median follow up time of 11.1 months, the median DOR had not been reached. Among the responding patients, 57% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer. The median duration of exposure to KEYTRUDA® was 4.9 months. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.

It was concluded that in patients with advanced solid tumors treated with KEYTRUDA® monotherapy, high TMB was associated with higher Objective Response Rates and median Duration of Response, with the Progression Free Survival favoring patients with high TMB. These data suggest that TMB may be predictive of the efficacy of KEYTRUDA® monotherapy in patients with a wide range of tumor types.

Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Marabelle A, Fakih MG, Lopez J, et al. Annals of Oncology (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253.

KEYTRUDA® (Pembrolizumab)

The FDA on June 16, 2020 granted accelerated approval to KEYTRUDA® for the treatment of adult and pediatric patients with unresectable or metastatic Tumor Mutational Burden-High (TMB-H) [10 or more mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. KEYTRUDA® is a product of Merck & Co., Inc.

Proton Based Chemoradiotherapy Significantly Decreases Toxicities without Compromising Efficacy

SUMMARY: Radiation Therapy involves the use of X-Rays, Gamma rays and charged particles for cancer treatment. External Beam Radiation Therapy (EBRT) is most often delivered using a linear accelerator in the form of Photon beams (either X-rays or Gamma rays). Photons have no mass and are packets of energy of an electromagnetic wave. Electrons and Protons are charged particles and Electrons are considered light particles whereas Protons are considered heavy particles. Electron beams are used to irradiate skin and superficial tumors, as they are unable to penetrate deep into the tissues. The different types of External Beam Radiation Treatments include 3-Dimensional Conformal Radiation Therapy (3D-CRT) meant to deliver radiation to very precisely shaped target areas, IMRT or Intensity Modulated Radiation Therapy which allows different areas of a tumor or nearby tissues to receive different doses of radiation, Image Guided Radiation Therapy (IGRT) which allows reduction in the planned volume of tissue to be treated, as changes in a tumor size are noted during treatment, Stereotactic RadioSurgery (SRS) which can deliver one or more high doses of radiation to a small tumor and Stereotactic Body Radiation Therapy (SBRT) or CYBERKNIFE® which is similar to SRS but also takes the normal motion of the body into account while treating malignancies involving the lung and liver.

Proton beams unlike Photons, enter the skin and travel through the tissues and deposit much of their energy at the end of their path (known as the Bragg peak), and deposit less energy along the way. This is unlike Photons which deposit energy all along the path through the tissues and the deposited dose decreases with increasing depth. As a result, with Proton beam therapy, normal tissues are exposed to less radiation compared with Photons. Despite this advantage, tissue heterogeneity such as organ motion, tumor volume changes during treatment can have a significant negative impact on target coverage for Proton beam therapy and can result in damage to the surrounding tissues and potential complications. It is well established that there is significant benefit for Proton beam therapy in certain pediatric malignancies.Types-of-Radiation-Therapy

Curative treatment with concurrent chemoradiotherapy is the standard of care for many nonmetastatic, locally advanced cancers. This treatment modality however is associated with substantial morbidity. Proton therapy as component of concurrent chemoradiotherapy might be able to reduce treatment related toxicity and achieve comparable cancer control outcomes, compared with conventional Photon radiotherapy, by reducing the radiation dose to normal tissues. There are however limited data comparing results of Proton chemoradiotherapy with Photon chemoradiotherapy, and Proton therapy remains unproven in this treatment setting. The objective of this study was to assess whether Proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer hospitalizations or other adverse events and similar Disease-free and Overall Survival, compared with concurrent Photon chemoradiotherapy.

In this large single-institution, nonrandomized, comparative effectiveness, retrospective analysis, 1483 adult patients with nonmetastatic, locally advanced cancer, treated with concurrent chemoradiotherapy with curative intent were included. Three hundred ninety-one patients (N=391) received Proton therapy and 1092 patients received Photon therapy. Common tumor sites included head and neck, lung, brain, esophagus/gastric, rectum, and pancreas. The median patient age was 62 years, but patients treated with Protons were significantly older with a median age of 66 years versus 61 years, had less favorable Charlson-Deyo comorbidity scores and had lower integral radiation dose to tissues outside the target. Ninety three percent (93%) of patients in the Photon therapy group were treated with Intensity-Modulated Radiotherapy (IMRT). Baseline ECOG Performance Status was similar between the two treatment cohorts. The Primary end point was 90-day adverse events associated with unplanned hospitalizations (CTCAE version 4 – Grade 3 or more). Secondary end points included ECOG performance status decline during treatment, 90-day adverse events of at least Grade 2 that limit instrumental activities of daily living, and Disease-Free and Overall Survival. The data on adverse events and survival were gathered prospectively.

It was noted that Proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse events of at least Grade 3 (P=0.002), significantly lower relative risk of 90-day adverse events of at least Grade 2 (P=0.006), and decline in Performance Status during treatment (P<0.001). Proton chemoradiotherapy was associated with a two-thirds reduction in adverse events associated with unplanned hospitalizations. At a median follow up of 3.7 years for the Proton cohort and 4.2 years for the Photon cohort, there was no difference in Disease-Free or Overall Survival.

It was concluded from this analysis that in adults with locally advanced cancer, Proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar Disease-Free and Overall Survival, compared to Photon therapy.
Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer. Baumann BC, Mitra N, Harton JG, et al. Jama Oncol. 2020;6:237-246.