Episode 2.01: Selinexor [2:55]

• FDA approves selinexor for refractory or relapsed multiple myeloma
  • Selinexor is a novel nuclear export inhibitor (NEI)

1. Adverse Events

   • In the clinical study that led to this drug approval, there was an 8.9% rate of fatal adverse events attributed to the drug
     • STORM Trial

2. Toxicity

   • Toxicity includes thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremia, infections, and neurological toxicity

3. RR

   • The overall response rate was 25.3%, with:
     • 1 stringent complete response
     • 4 very good partial responses
     • 16 partial responses
   • It is important to remember that reduction of serum M-protein response to therapy (< 50% reduction) is a surrogate

   

   • Just because the patients have progressed through 5 options does not mean selinexor is their last option
     • There are many other cytotoxic options

4. Additional Thread

   

   

   • Dr. Rajkumar's mention of the BELLINI trial was a good move
     • There was a negative correlation between the surrogates and survival in this study
       • It is proof that surrogates are fallible

5. Counterarguments

   

• Dr. Leonard makes a very good point–the FDA is not mandating the use of selinexor
  • In other words–why would the FDA want to get in the way of a patient who still wants to use the drug after an informed discussion?
    • This shows that the FDA has staked out a position that's quite untenable
• Dr. Prasad states that the informed discussion system has flaws:

  1. The response rate and death rate values approved by the FDA are arbitrary

     "Why do we let a government bureaucrat draw some line that a 20% response rate is okay, and a 10% death rate is okay, but a 40% death rate is not okay? Why not? It's up to the person </s>." - Dr. Prasad

  2. Vulnerable and sick patients are prone to making choices out of desperation, or hope, that are actually not compatible with their true desires or goals

6. Danger in Oncology

• A functioning cancer drug system can't exist when oncologists are not saying "this is not good enough"
  • If there is not pushback–the bar remains far too low

• Consistently lowering the bar, and not enforcing logical standards of drug approval will destroy the agency
  • When a bureaucracy is imposed, and it fails to yield benefit, it will be eliminated

7. Uncertainty in the Marketplace

• By speeding drugs to market–researchers are adding uncertainty to the establishment

  • Studies need to measure OS or QoL and using surrogate endpoints in late lines of therapy does not save time

    

    Chen et al.

Episode 2.01: ECHELON-2 [33:07]

• Conversation with Dr. John Reneau
  • Dr. Reneau earned his M.D. from the Texas A&M Health Science Center College of Medicine
    • He completed his internal medicine residency at the Mayo Clinic and fellowship in hematology/oncology at the University of Michigan
      • He is a soon-to-be attending at Ohio State University
  • His twitter handle is @LymphomaMD
  • Book recommendation by Dr. Prasad
    • Henry Kaplan and the Story of Hodgkin's Disease
• T-cell Lymphoma's
  • T-cell lymphomas represent about 10 to 15% of all lymphoma diagnoses in the United States
    • Although these types of lymphomas are rare, t-cell lymphomas are divided into about 30 different buckets
      • The most prevalent is called peripheral T-cell lymphoma
        • Other common types:
          • Angioimmunoblastic T-cell lymphoma (AITL)
          • anaplastic large cell lymphoma (PCALCL)
            • ALK +/-
• When does Dr. Reneau use etoposide?
  • Although controversial–there are retrospective studies looking at the utility in combination with CHOP chemotherapy
    • Only a PFS benefit in patients younger than 60
• Dr. Reneau's considerationof the the role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) ?
  • For most patients, Dr. Reneau considers autotransplant except on a few conditions:
    • ALK + patients already do well so transplant is typically not performed
    • He also doesn't tend to transplant patients with low risk, early stage lymphomas
• Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2) [42:14]
  • Published in The Lancet
    • 452 patients were randomized to receive either A+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) or CHOP
• Inclusion criteria and Patient Population
  • Subjects needed to be CD30-positive (≥10% of cells by local review)
  • The percent of patients who had anaplastic large cell lymphoma (ALCL) was extraordinarily high in this trial
    • The researchers had to enrich the population with ALCL, vs. PLCL, in order to obtain adequate CD30 expression