After the life changing immuno and targeted therapy developments for melanoma patients back in 2011 and a bit beyond, not much new has made our lives substantially better since. I've been reporting on anti-LAG-3 since 2014. Anti-LAG-3 reports! Currently the anti-LAG-3 product Relatlimab is in trials and continues to look promising. Here are a couple of reports from last year: Something "new" in melanoma treatment???? Anti-LAG-3! Again...
Now, there's this:
Relatlimab and Nivolumab versus Nivolumab in Untreated
Advanced Melanoma. Tawbi,
Schadendorf, Lipson, Ascierto…Hodi, Long.
N Eng J Med. Jan 2022.
Background: Lymphocyte-activation gene 3 (LAG-3) and
programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that
contribute to T-cell exhaustion. The combination of relatlimab, a
LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been
shown to be safe and to have antitumor activity in patients with previously
treated melanoma, but the safety and activity in patients with previously
untreated melanoma need investigation.
Methods: In this phase 2-3, global, double-blind, randomized
trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as
compared with nivolumab alone when administered intravenously every 4 weeks to
patients with previously untreated metastatic or unresectable melanoma. The
primary end point was progression-free survival as assessed by blinded
independent central review.
Results: The median progression-free survival was 10.1
months (6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (3.4
to 5.6) with nivolumab. Progression-free survival at 12 months was 47.7% (41.8
to 53.2) with relatlimab-nivolumab as compared with 36.0% (30.5 to 41.6) with
nivolumab. Progression-free survival across key subgroups favored
relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse
events occurred in 18.9% of patients in the relatlimab-nivolumab group and in
9.7% of patients in the nivolumab group.
Conclusions: The inhibition of two immune checkpoints, LAG-3
and PD-1, provided a greater benefit with regard to progression-free survival
than inhibition of PD-1 alone in patients with previously untreated metastatic
or unresectable melanoma. Relatlimab and nivolumab in combination showed no new
safety signals.
Relatlimab plus nivolumab improves progression-free
survival in metastatic melanoma.
MD Anderson News Release, Jan 5, 2022.
In patients with untreated, advanced melanoma, the
combination of immune checkpoint inhibitors relatlimab and nivolumab doubled
the progression-free survival benefit compared to nivolumab alone, with a
manageable safety profile, according to the results of the Phase II/III RELATIVITY-047 clinical trial reported by The
University of Texas MD Anderson Cancer Center today in the New England Journal
of Medicine.
Median progression-free survival was 10.1 months in the
combination arm and 4.6 months in the monotherapy arm. After 12 months’
follow-up, progression-free survival rates were 47.7% in the combination arm
versus 36% in the monotherapy arm, with a 25% lower risk of disease progression
or death in the combination arm. The benefit of the combination therapy was
observed across pre-specified subgroups. The Food and Drug Administration
granted priority review to the combination in September 2021 based on the
results of this study.
“The results from this global effort advance the field of
immunotherapy by establishing a third class of immune checkpoint inhibitors
through the LAG-3 pathway and have the potential to be practice-changing,” said
lead author Hussein Tawbi, M.D., Ph.D., professor of Melanoma Medical Oncology.
“We’ve seen historic developments in melanoma treatment over the last decade
with the combination of PD-1 and CTLA-4 inhibitors, which work well but also
carry substantial toxicity. This study represents a significant and
long-awaited next step toward providing patients with effective and safer
treatment options.”
Relatlimab is a novel antibody that blocks
lymphocyte-activation gene 3 (LAG-3), an immune checkpoint found on the surface
of T cells. LAG-3 is often upregulated in melanoma, as is programmed death-1
(PD-1), the immune checkpoint inhibited by nivolumab. These data represent the
first Phase II/III clinical trial results of a third-generation checkpoint
inhibitor and the first clinical trial designed to compare combination
checkpoint inhibitor therapy versus nivolumab monotherapy in melanoma.
Currently, PD-1 and CTLA-4 inhibitor monotherapy and
combination therapy are approved frontline treatment options for metastatic
melanoma. The combination therapies benefit more patients than monotherapy, but
also greatly affect quality of life, with toxicity rates of more than 50%.
In this study, grade 3 or 4 treatment-related adverse events
occurred in 18.9% of patients in the combination arm and 9.7% in the
monotherapy arm. The most common grade 3 or 4 events included increased levels
of pancreatic and liver enzymes, and fatigue. Investigators determined three
deaths in the combination arm and two deaths in the monotherapy arm were
treatment-related. Immune-mediated adverse events included hypothyroidism/thyroiditis,
rash and colitis. No new safety signals were identified, and patients rated
their health-related quality of life similarly across both treatment arms.
The trial enrolled 714 patients with untreated, unresectable
stage III or IV melanoma across 111 international sites between May 2018 and
December 2020. Patients were randomized to receive relatlimab and nivolumab or
nivolumab alone once every four weeks. Sixty patients (8.4%) received prior
targeted therapy or immunotherapy as adjuvant therapy at least six months
before recurrence, or received interferon six weeks before randomization. The
median age of participants was 63; 41.7% were female and 96% were white.
At the time of data cutoff (March 9, 2021), median follow-up
was 13.2 months, with 470 patients (65.8%) having discontinued treatment. The
top reason for discontinuation was disease progression (36.3% in the
combination arm and 46% in the monotherapy arm).
The study met its primary endpoint of blinded independent
central review-assessed progression-free survival, with progression defined as
tumor growth or death due to any cause. The benefit was sustained across
pre-defined subgroups, including BRAF status, tumor stage, lactate
dehydrogenase (LDH) levels and LAG-3 and PD-1 expression.
“We now have evidence of a clear benefit for combination
therapy compared to single-agent PD-1 inhibitors, and we’re looking forward to
seeing response and overall survival data,” Tawbi said. “We’re also thinking
about the populations that were excluded from this trial, including those with
untreated brain metastases and uveal melanoma, so that all patients can have a
chance to take advantage of the progress we’re making against melanoma.”
Hang tough, ratties! ~ c
