Combination therapy developed by NIH researchers demonstrates
the power of precision medicine.
BETHESDA, Md., June 19,
2024 /PRNewswire/ -- Researchers at the National
Institutes of Health (NIH) have developed a non-chemotherapy
treatment regimen that is achieving full remissions for some people
with aggressive B-cell lymphoma that has come back or is no longer
responding to standard treatments. The five-drug combination
targets multiple molecular pathways that diffuse large B-cell
lymphoma (DLBCL) tumors use to survive.
In a clinical trial at NIH's National Cancer Institute,
researchers tested the combination of venetoclax, ibrutinib,
prednisone, obinutuzumab, and lenalidomide (called ViPOR) in 50
patients with DLBCL, the most common type of lymphoma. The
treatment shrank tumors substantially in 26 of 48 (54%) evaluable
patients, with 18 (38%) of those patients' tumors disappearing
entirely, known as a complete response. At two years, 36% of all
patients were alive and 34% were free of disease. These benefits
were seen mainly in people with two specific subtypes of DLBCL.
The findings were published June 20,
2024, in the New England Journal of
Medicine.
"Many of these patients who stopped responding to standard
treatments would have otherwise died within a year, and now we have
a good proportion who are still alive past two years, and some past
four years," said Christopher J.
Melani, M.D., of NCI's Center for Cancer Research, who
co-led the study. "It's gratifying to see these long-term
remissions and potential cures in patients."
Previous studies have identified various genetic pathways
involved in the development and survival of the different molecular
subtypes of DLBCL, such as activated B cell–like (ABC) DLBCL and
germinal center B cell–like (GCB) DLBCL. Targeted drugs have shown
effectiveness in blocking some of these pathways, but individual
drugs rarely produced lasting responses in patients because the
tumors may be resistant due to alternative survival pathways. Dr.
Melani and his colleagues hypothesized that combining targeted
drugs that block multiple survival pathways would lead to more
durable responses.
Based on laboratory studies in which they analyzed which
targeted drugs could best be combined to kill DLBCL cells in a
synergistic manner, the researchers designed the five-drug regimen
to test in human trials. To allow for the targeted drugs to work
synergistically in patients, the researchers gave the drugs
simultaneously in two-week cycles. To limit the accumulation of
side effects, they scheduled a weeklong break between each
cycle.
"DLBCL is one of the most genetically heterogeneous forms of
cancer, and as a result we don't yet have the ability to identify
exactly which combination of drugs would be most effective for any
given patient," Dr. Melani said. "By putting five drugs together,
we believe that there will be some drug combination—either two,
three, or more drugs—that will be particularly effective against
that patient's tumor."
In the phase 1b/2 trial, 50 people
with DLBCL that had relapsed or stopped responding to treatment
were given six cycles of the ViPOR regimen. Responses to ViPOR
varied by DLBCL subtype, with complete responses concentrated in
two subtypes, including in 8 of 13 (62%) people with non-GCB DLBCL
and 8 of 15 (53%) people with a form of GCB DLBCL known as
high-grade B-cell lymphoma "double hit."
At two years, people with non-GCB DLBCL and double-hit GCB DLBCL
had higher rates of both progression-free and overall survival than
other people in the study. Non-GCB DLBCL and double-hit GCB DLBCL
are highly reliant on the survival mechanisms targeted by ViPOR, so
it makes sense that they responded particularly well to the
combination therapy. ViPOR also helped 6 of 20 (30%) patients whose
lymphomas had not responded to or had come back after CAR T-cell
therapy—the current standard of care for people with relapsed
DLBCL—achieve lasting remissions.
Side effects of the five-drug regimen were generally mild to
moderate when compared with those of standard treatments and
improved during the treatment breaks. Only five patients had to
stop treatment early for various reasons, including side effects.
Given these relatively mild to moderate side effects, additional
drugs could potentially be added to ViPOR to improve its efficacy,
the researchers said. The team is also studying the ViPOR regimen
in people with other types of lymphoma that are resistant to
previous therapies.
The researchers have developed a larger phase 2 study, which
will be conducted at multiple centers, to confirm the activity of
ViPOR in people with non-GCB DLBCL and double-hit GCB DLBCL.
More work is needed to develop therapies for GCB DLBCL subtypes
that aren't as responsive to ViPOR.
NCI's Center for Cancer Research investigators Wyndham H. Wilson, M.D., Ph.D., Mark Roschewski, M.D., and Louis M. Staudt, M.D., Ph.D., co-led the study
with Dr. Melani. Investigators from NIH's National Center for
Advancing Translational Sciences and other institutions contributed
to the study.
About the National Cancer Institute (NCI): NCI leads the
National Cancer Program and NIH's efforts to dramatically reduce
the prevalence of cancer and improve the lives of people with
cancer. NCI supports a wide range of cancer research and training
extramurally through grants and contracts. NCI's intramural
research program conducts innovative, transdisciplinary basic,
translational, clinical, and epidemiological research on the causes
of cancer, avenues for prevention, risk prediction, early
detection, and treatment, including research at the NIH Clinical
Center—the world's largest research hospital. Learn more about the
intramural research done in NCI's Center for Cancer Research. For
more information about cancer, please visit the NCI website at
cancer.gov or call NCI's contact center at 1-800-4-CANCER
(1-800-422-6237).
About the National Institutes of Health (NIH): NIH,
the nation's medical research agency, includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. NIH is the primary federal agency conducting and
supporting basic, clinical, and translational medical research, and
is investigating the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs,
visit nih.gov.
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