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FDA APPROVES DABRAFENIB PLUS TRAMETINIB FOR BRAF V600E–MUTATED UNRESECTABLE OR
METASTATIC SOLID TUMORS

June 22, 2022
Kristi Rosa






The FDA has granted an accelerated approval to dabrafenib plus trametinib for
the treatment of adult and pediatric patients aged 6 years and older with
unresectable or metastatic solid tumors harboring a BRAF V600E mutation who have
progressed following previous treatment and who have no satisfactory alternative
treatment options.



FDA



The FDA has granted an accelerated approval to dabrafenib (Tafinlar) plus
trametinib (Mekinist) for the treatment of adult and pediatric patients aged 6
years and older with unresectable or metastatic solid tumors harboring a BRAF
V600E mutation who have progressed following previous treatment and who have no
satisfactory alternative treatment options.1

The regulatory decision was supported by clinical efficacy and safety data
observed in 3 clinical trials. In the phase 2 ROAR basket study (NCT02034110)
and arm H of the NCI-MATCH study (NCT02465060), the doublet resulted in overall
response rates of up to 80% in patients with BRAF V600E–mutated solid tumors,
including high- and low-grade glioma, biliary tract cancer and select
gynecological and gastrointestinal cancers.2 Moreover, an additional study,
Study X2101 (NCT02124772), demonstrated the clinical benefit and acceptable
toxicity profile of the combination in pediatric patients.2

“The combination of dabrafenib and trametinib demonstrated meaningful efficacy
in multiple BRAF-positive tumor types, including in some patients with rare
cancers who have no other treatment options available,” Vivek Subbiah, MD,
principal investigator and associate professor of Investigational Cancer
Therapeutics and center medical director of the Clinical Center for Targeted
Therapy in the Division of Cancer Medicine at The University of Texas MD
Anderson Cancer Center, stated in a press release. “Physicians should consider a
BRAF test as a routine diagnostic step that could enable a new option for
treating patients with many solid tumors.”

The multi-cohort, multicenter, non-randomized, open-label ROAR trial included
adult patients with selected tumors harboring BRAF V600E mutation; this included
those with high-grade glioma (n = 45), biliary tract cancer (n = 43), low-grade
glioma (n = 13), adenocarcinoma of small intestine (n = 3), gastrointestinal
stromal tumor (n = 1), and anaplastic thyroid cancer.

Patients were enrolled based on local assessments of BRAF V600E mutation status.
Moreover, BRAF mutation was confirmed via central laboratory in 93 of 105
patients.

Arm H of the single-arm, open-label NCI-MATCH study also enrolled patients with
a BRAF V600E mutation. Here, patients with melanoma, thyroid cancer, or
colorectal cancer were excluded, and BRAF V600E mutational status for enrollment
was determined either by central or local laboratory test.

The study included adult patients with solid tumors such as gastrointestinal
tumors (n = 14), lung cancers (n = 7), gynecologic or peritoneal tumors (n = 6),
central nervous system tumors (n = 4), and ameloblastoma of mandible (n = 1).

Among the 131 patients enrolled ito both trials, the median age at baseline was
51 years, with 20% of patients aged 65 years or older. Moreoverf, 56% of
patients were female; 85% were White, 9% were Asian, and 3% were Black. The
majority of patients (56%) had an ECOG performance status of 1, 37% had a status
of 0, and 6% had a status of 2. Of the 131 patients, 90% received prior systemic
therapy.



Additional data from these trials showed that the objective response rate (ORR)
achieved with the combination in those with biliary tract cancer (n = 48) was
46% (95% CI, 31%-61%), with a median duration of response (DOR) of 9.8 months
(95% CI, 5.3-20.4). In those with high-grade glioma (n = 48), the ORR was 33%
(95% CI, 20%-48%), with a median DOR of 13.6 months (95% CI, 5.5-26.7).

In those with low-grade glioma (n = 14), the ORR achieved with the doublet was
50% (95% CI, 23%-77%), with a DOR ranging from 6 months to 29 months. Moreover,
dabrafenib plus trametinib resulted in ORRs of 80% and 50% in those with
low-grade serous ovarian cancer (n = 5) and those with adenocarcinom of the
small intestine (n = 4), respectively; the median DORs ranged from 12 months to
42 months, and 7 months to 8 months, respectively.

The multicenter, open-label, multiple cohort Study X2101 included pediatric
patients with refractory or recurrent solid tumors. Part C was a dose escalation
of dabrafenib in combination with trametinib in patients whose tumors harbored a
BRAF V600E mutation. Part D was a cohort expansion phase of dabrafenib in
combination with trametinib in patients with low-grade glioma and a BRAF V600E
mutation.

The major efficacy outcome measure was ORR per ndependent review committee
assessment and by RANO criteria. The efficacy of the doublet was examined in a
total of 48 pediatric patients; 34 of these patients had low-grade glioma and 2
had high-grade glioma. For those with BRAF V600E–mutated low-grade glioma and
high-grade glioma in parts C and D, respectively, the median age was 10 years
(range, 1-17) and 50% were male. Moreover, 75% of patients were White, 8% were
Asian, and 3% were Black. Fifty-eight percent of patients had a Karnofsky/Lansky
performance status of 100.

Eighty-three percent of patients previously underwent surgery, 2.8% had prior
external beam radiotherapy, and 92% previously received systemic therapy. Data
showed that the combination elicited an ORR of 25% (95% CI, 12%-42%). For the 9
responders, the DOR was 6 months or longer for 78% of patients and 24 months or
longer for 44% of patients.

The toxicity profile of the combination observed in these studies was consistent
with the known profile in other approved indications.

“Tackling cancer is complex, which is why it is so important that we continue to
follow the science as we pursue meaningful advances and new approaches to
treating cancer,” Reshema Kemps-Polanco, head of Novartis Oncology US, added in
the press release. “We are grateful to the patients, and to the multitude of
individuals and teams working together to make this latest approval possible as
we strive to do more for more people living with cancer.”


REFERENCES

 1. Novartis Tafinlar + Mekinist receives FDA approval for first tumor-agnostic
    indication for BRAF V600E solid tumors. News release. Novartis Pharma AG.
    June 22, 2022. Accessed June 22, 2022. https://bit.ly/3tW25BN
 2. Tafinlar. Prescribing information. East Hanover, NJ: Novartis
    Pharmaceuticals Corp; 2022. Accessed June 22, 2022. https://bit.ly/3HM4IMv






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