Takeda’s EXKIVITY™ (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC

  • Approval based on Phase 1/2 trial results, which demonstrated clinically meaningful responses with a median duration of response (DoR) of approximately 1.5 years
  • Next-generation sequencing (NGS) companion diagnostic test approved simultaneously to support identification of patients with EGFR Exon20 insertion mutations

OSAKA, Japan, and CAMBRIDGE, Mass. September 15, 2021 – Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that the U.S. Food and Drug Administration (FDA) has approved EXKIVITY (mobocertinib) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. EXKIVITY, which was granted priority review and received Breakthrough Therapy Designation, Fast Track Designation and Orphan Drug Designation from the FDA, is the first and only approved oral therapy specifically designed to target EGFR Exon20 insertion mutations. This indication is approved under Accelerated Approval based on overall response rate (ORR) and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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Written by: Joshua Nubla, PharmD, NCODA
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Description: The purpose of this PQI is to discuss Stage III Non-small cell lung cancer (NSCLC) and patient eligibility.

Background: Within the category of Lung Cancer, approximately 80% to 85% of lung cancers are NSCLC.3,5 Treatment for stage III NSCLC may include combinations of radiation, chemotherapy, and/or surgery, which requires input from the medically integrated team, including medical and radiation oncologists along with thoracic surgeons. Concurrent chemoradiation therapy (CRT) is often utilized when patients with Stage III NSCLC either decline or are ineligible for surgical options.4 Immunotherapy is possible to be given at this stage with durvalumab being the standard of care in patients who have not progressed after 2 or more cycles of definitive concurrent CRT. Meta-analysis has shown that concurrent CRT confers significant benefit when it comes to long-term survival of patients with for NSCLC (2,3,4, and 5-year survival rates).6 NCCN guidelines suggest use of durvalumab as the Category 1 recommendation in unresectable Stage III NSCLC following definitive CRT.2 Initiation of durvalumab following CRT may also elicit a synergistic antitumor immune response, given the mechanism of durvalumab as a monoclonal antibody that binds to programmed cell death ligand-1 (PD-L1), thereby blocking the PD-L1/PD-1 immune checkpoint signaling cascade.8-13 Based on the PACIFIC study criteria approximately 70% of patients with unresectable stage III NSCLC would be eligible to receive durvalumab following CRT.7 If initiating durvalumab, therapy care teams are instructed to begin therapy within 42 days after CRT completion.1

PQI Process:

    • Consider durvalumab for Non-small Cell Lung Cancer (NSCLC) if ALL of the following criteria are met:
      • Individual is 18 years of age or older
      • Individual has not received previous therapy with a PD-L1/PD-1 unless otherwise specified
      • Used as a single agent
      • Used as consolidation therapy
      • Disease is unresectable stage III without progression after 2 or more cycles of definitive CRT
      • Individual has performance status (PS) 0-1 (World Health Organization grading)
        • 0-1 PS: able to perform all pre-disease activities without restriction or restricted when engaging in physical activity but able to carry out light work
      • If durvalumab is an option, especially with concurrent CRT, plan to initiate within 42 days of CRT

    Patient Centered Activities:

    • Review with patient potential options for stage III NSCLC
      • Review PQI Durvalumab (Imfinzi®) Therapy Overview for management guidance
      • Counsel patient on immune-mediated adverse event (imAE) symptoms and when to report symptoms to oncologist
      • Schedule regular visits for blood tests (CBC, renal, hepatic, pancreatic, thyroid) and monitoring
      • Consider early initiation of steroids as necessary

Supplemental Information:

Diagram of durvalumab’s current place in therapy for NSCLC2

References:

  1. Imfinzi (durvalumab) [prescribing information]. Wilmington, DE. AstraZeneca Pharmaceuticals LP.; 2021
  2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2021.
  3. American Cancer Society. https://www.cancer.org/cancer/lung-cancer/about/what-is.html. Accessed March 2021
  4. American Cancer Society. https://www.cancer.org/cancer/lung-cancer/treating-non-small-cell/by-stage.html. Accessed March 2021
  5. Chiramel J., Tay R., Califano R. Durvalumab after chemo-radiotherapy in stage III non-small cell lung cancer. J Thorac Dis. 2018;10(Suppl 9):S991–S994.
  6. Xiao W, Hong M. Concurrent vs sequential chemoradiotherapy for patients with advanced non-small-cell lung cancer: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2021 Mar 19;100(11):e21455.
  7. Sakaguchi T, Ito K, Furuhashi K, Nakamura Y, Suzuki Y, Nishii Y, Taguchi O, Hataji O. Patients with unresectable stage III non-small cell lung cancer eligible to receive consolidation therapy with durvalumab in clinical practice based on PACIFIC study criteria. Respir Investig. 2019 Sep;57(5):466-471.
  8. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203(5):1259-1271.
  9. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74(19):5458-5468.
  10. Deng L, Liang H, Burnette B, et al. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687-695.
  11. Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti–PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3(9):1052-1062.
  12. Hato SV, Khong A, de Vries IJ, Lesterhuis WJ. Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res. 2014;20(11):2831-2837.
  13. Ibrahim R, Stewart R, Shalabi A. PD-L1 blockade for cancer treatment: MEDI4736. Semin Oncol. 2015;42(3):474-483.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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Written By: Todd Murphree, PharmD Clearview Cancer Institute
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Description of PQI: Ruxolitinib is a selective Jak2 inhibitor used for the treatment of myelofibrosis (MF). This PQI will review the close monitoring of platelets required to ensure appropriate dose and avoid severe thrombocytopenia due to the therapy.

Background: Ruxolitinib is FDA approved for the treatment of intermediate or high-risk patients with MF. This includes patients with primary MF, post polycythemia vera MF, and post-essential thrombocytopenia MF.

PQI Process: Pharmacy management of patients’ labs to ensure correct dosing of ruxolitinib can contribute to increased efficacy and decreased toxicity of the therapy. When receiving a new prescription for ruxolitinib:

  • Review dosing
    • Dosing is based on baseline platelet count and platelet counts must be monitored throughout therapy
Baseline Platelet CountRuxolitinib Dose
>200 x 109 cells/L20 mg BID
100 to 200 x 109 cells/L15 mg BID
50 to 99 x 109 cells/L5 mg BID

 

  • Check for drug-drug interactions
  • Lab Monitoring
    • CBC/CMP – baseline, every 2 to 4 weeks until dose is stabilized, then as clinically indicated
    • Lipid panel – Baseline and 8 to 12 weeks after initiation
  • Ensure the patient has follow up labs scheduled appropriately (see lab monitoring section)
    • Add reminders in pharmacy management software or EMR for follow-up on patient’s labs every 2-4 weeks until dose is stabilized (usually within 8 weeks)
  • Refills will be filled only after:
    • CBC has been checked
    • Platelet count has been evaluated for appropriateness of dose

Dose Modifications:

  • Do not adjust dose within the first 4 weeks, and no more than every 2 weeks thereafter
    • Dose may be increased by 5 mg BID increments to a max dose of 25 mg BID if:
      • Failure to achieve a reduction from baseline spleen length of 50% or a 35% reduction in spleen volume as measured by CT or MRI
      • Platelet count more than 125 x 109 cells/L at treatment week 4 and platelet counts never less than 100 x 109 cells/L
      • ANC more than 0.75 x 109 cells/L
    •  Discontinue ruxolitinib if spleen size reduction or symptom improvements not observed after 6 months of therapy
    • When discontinuing therapy for any reason other than thrombocytopenia, consider gradually tapering dose by 5 mg twice daily each week
  • Evaluate platelet count and may recommend the following dose adjustments to provider:

Baseline Platelet Count of 100 x 10(9) cells/L or Higher: 1

Current Platelet CountDose Adjustment
125 x 109 cells/L or higherNo dose adjustment
100 to 124 x 109 cells/LIf starting dose was 20 mg BID, decrease dose by 5 mg BID

If starting dose was 15 mg BID or less, no adjustment needed

75 to 99 x 109 cells/LDecrease dose to 10 mg BID

If starting dose was 10 mg BID or less, no adjustment needed

50 to 74 x 109 cells/LDecrease to 5 mg BID

If starting dose was 5 mg BID, no adjustment needed

<50 x 109 cells/LHold. May restart when platelets >50 x 109 cells/L

Baseline Platelet Count of 50 to 99 x 109 cells/L: 1

Current Platelet CountDose Adjustment
25 to 35 x 109 cells/L and platelet decline during prior 4 weeks is less than 20%Decrease total daily dose by 5 mg.

For patients on 5mg once daily prior to decline, continue same dose

25 to 35 x 109 and platelet decline during prior 4 weeks is 20% or higherDecrease dose to 5mg BID

If dose is 5 mg BID, decrease to 5 mg once daily

If dose is 5 mg once daily, continue same dose

<25 x 109Hold therapy

May restart when platelets >35 x 109 cells/L starting with 5 mg BID less than previous dose

 

Patient Centered Activities:

  • Provide Oral Chemotherapy Education (OCE) sheet
  • Stress importance of adherence
    • The only way to achieve the proper patient-specific dose is if the patient is adherent
    • Schedule follow-up calls
  • Provide education:
  • Laboratory monitoring
  • Possibility of dose adjustments based on labs
  • Monitoring Skin:
    • Important to note all skin lesions
      • Examine skin at baseline
      • Make note of any new lesions that arise while on therapy

References:

  1. Jakafi® (ruxolitinib) Package Insert.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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