Unfortunately, as mentioned in yesterday's post, current melanoma treatments do not meet the needs of all melanoma patients. Also as mentioned, a great deal of current research is building on existing immunotherapies - attempting to fortify response rates by adding a wide variety of pharmaceuticals to existing products.
Here is another study looking at combining an anti-LAG-3 product with yet another anti-PD-1 product: (Note: Yesterday's post includes a link to previous data and info about anti-LAG-3 generally.)
Clinical activity of fianlimab (REGN3767), a human
anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in
patients (pts) with advanced melanoma.
Hamid, Wang, Kim, et al. ASCO
2021.
Background: Fianlimab
and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4
monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined
with cemiplimab showed an acceptable safety profile and some clinical activity
in pts with advanced malignancies. Here, we present safety and clinical
activity data from two expansion cohorts of pts with advanced melanoma
(anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who
were treated with fianlimab + cemiplimab and had an opportunity for first
on-treatment tumor assessment (cut-off date: Jan 4, 2021).
Methods: Pts with
advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior
anti–PD-(L)1 treatment within 3 months of screening (experienced) received
fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor
measurements were performed every 6 weeks for the first 24 weeks and
subsequently every 9 weeks per RECIST v1.1.
Results: 48 pts with
advanced melanoma were treated with the combination therapy: 33 were
anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years
vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile
(including immune-related adverse events [AEs]) of fianlimab + cemiplimab
combination therapy was similar to that of anti–PD-1 monotherapy with one
exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to
the rate previously observed with anti–PD-1 + anti–cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than
that observed with anti–PD-1 monotherapy. Grade greater than/= to treatment-emergent AEs
(TEAEs) occurred in 35.4% (17/48) of patients; Grade greater than/= to serious TEAEs occurred
in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment
due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n =
11, 22.9%). By investigator assessment, objective response rate (includes
unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18
PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1
experienced pts. Median progression-free survival and median duration of
response for the anti–PD-(L)1 treatment naïve cohort have not been reached.
Prognostic clinical markers and tumor biomarkers such as expression of LAG-3,
PD-L1, and major histocompatibility complex II are being evaluated. Recruitment
is ongoing.
Conclusions: The
safety profile of fianlimab + cemiplimab is similar to that observed with
cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate
of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical
activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4
combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial
information: NCT03005782.
Fingers crossed!
With its 50%+ response rate and durable results, the ipi/nivo combo has thus far been the best thing going for melanoma patients. However, side effects caused by the treatment force roughly 40% of patients to discontinue therapy. (With that in mind, you may find this report from 2017 of interest: 40% of melanoma patients stop ipi/nivo due to side effects...BUT...efficacy is about the same!!!) Anyhow, in an effort to DECREASE those side effects, this trial is adding tocilizumab - a monoclonal antibody that blocks interleukin 6 and is often used to treat rheumatoid arthritis - to the combo. Interesting too, to look back on the addition of leflunomide (another drug used for RA) to targeted therapy as noted in this post: An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib?)
Ipilimumab, nivolumab and tocilizumab as first-line
therapy for advanced melanoma. Mehmi,
Hamid, Hodi, et al. ASCO 2021.
Background:
Interleukin 6 (IL-6) functions in the maintenance of hepatocytes,
haemotopoietic progenitor cells, a variety of other tissues, and regulates the
innate and adaptive immune system. IL-6 may play a role as a chronic
inflammatory mediator in altering levels of acute phase proteins synthesized by
the liver and circulating myeloid cells which have been shown to be associated
with short survival with checkpoint inhibition and which are immune
suppressive. The immunomodulatory properties of interleukin-6 may in part also
be responsible for immune related adverse events, given the reversal of those
toxicities observed with IL-6 receptor blockade in clinical practice. To assess
if blockade of IL-6 binding is associated with a decrease in irAEs and/or an
increase in efficacy defined as overall response rate (ORR) at week 24 in
patients receiving ICB, we added tocilizumab to ipilimumab and nivolumab
therapy.
Methods: The current
phase II trial is a two-stage design to assess the safety, tolerability, and
grades 3-5 immune related toxicities of tocilizumab administered every 6 weeks
up to week 24 in combination with ipilimumab at 1 mg/kg and nivolumab at 3
mg/kg every 3 weeks for 4 doses each during a 12 week induction period, then
administered every 6 weeks with nivolumab at 240 mg flat dose every 2 weeks in
maintenance for up to 24 weeks, and nivolumab alone will be given at 480 mg
flat dose every 4 weeks thereafter for up to 2 years. Eligible patients include
those age 18 or older with measurable and unresectable stages III/IV melanoma
(cutaneous, acral, mucosal), without prior systemic treatment for metastatic
disease. Adjuvant therapy (IFN-alpha, ipilimumab and/or nivolumab, or
pembrolizumab) is allowed. Patients with metastatic melanoma of brain are
allowed, if neurologically stable and off immunosuppressive steroids. A total
of 18 patients will be treated in the first stage, and 49 additional patients
in the second stage for a total of 67. The comparator data are from the N3I1
arm of Checkmate-511 trial, in which treatment-related grades 3-5 irAEs were
33.9% with a 45.6% response rate (1). Prespecified activity goal for the first
stage of accrual has been met; second stage accrual began in January 2021. Clinical trial information:
NCT03999749.
For what it's worth. - c
P.S. With great thanks to the Edster - this link, that includes an explanatory video from the Wizard Weber, gives important background on the whys and wherefores related to IL-6 in this instance and indicates that adding an IL-6 blockade may not only decrease side effects from immunotherapy but ADD effectiveness - Elevated Levels of Serum CRP and IL-6 Are Biomarkers of Poor Prognosis in Patients Receiving Immune Checkpoint Inhibitors. Gotta love a man in a bow tie who can elucidate the difference between predictive and prognostic!!!! - c
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