xenografts.46 Clinical data from PT-2385 in pretreated
patients with metastatic clear cell renal carcinoma
(mRCC) were encouraging in a Phase I, dose-escalation
trial, and demonstrated a favorable safety profile.47
PT2977/MK-6482 is the second generation of the HIF2
inhibitor and was tested in a 55 patient phase Ib-II
study.48 This study, which was presented at the European
Society of Medical Oncology meeting in the fall of
2019, described 55 patients with advanced cc RCC who
had received at least one prior therapy and who were
treated with 120 mg orally once daily dose of
PT2977/MK6482. We found that PT2977/MK6482 was
well tolerated and had a favorable safety profile. The
most common Grade 3 adverse events and on-target effects
of HIF2 inhibition were found to be anemia in 26%
of patients and hypoxia in 15%, and only 2 patients experienced
grade 4 toxicities. Despite having a study population
treated with a median of three prior therapies,
the ORR was 24%, the median progression-free survival
(PFS) was an impressive 11 months (95% CI 6-17), and
the 12-month PFS rate was 49%. PT2977/MK6482 is currently
being tested in a randomized phase III study in
patients with treatment refractory metastatic ccRCC
(NCT04195750).
P2977/MK6482 is also being tested in patients with
VHL disease (NCT03401788). This study has completed
accrual, and the data are maturing. As there is currently
no Food and Drug Administration approved therapy for
VHL disease, we are anxiously awaiting the outcome of
this trial to see if there is a potential registrational path
for this agent in the treatment of VHL disease.
Recently, the approval of combination TKI- checkpoint
blocking antibody therapy has resulted in a new
treatment paradigm for many patients with ccRCC. 49,50
Tissue based studies suggest antiangiogenic agents are capable
of increasing T-cell recruitment to the tumor microenvironment,
51 providing a mechanistic rationale for
this type of combination therapy. Further investigations
into the way VHL-HIF targeting agents can synergize
with checkpoint blocking antibodies will undoubtedly
further improve the treatment of patients with RCC.
Concluding Remarks
The seminal work by Drs. Semenza, Ratcliffe and Kaelin
have fundamentally changed our understanding of
ccRCC biology and ushered in a completely new treatment
paradigm for this disease and others. Elucidating
the functional consequences of VHL loss has not only
shed light on how cells sense and adapt to a hypoxic environment
but has also paved the way for the development
of a new class of target based therapeutic strategies
to treat ccRCC. Although therapeutic agents targeting
VEGF and VEGF receptors have demonstrated robust efficacy
in clinical trials, few people have been cured. We
await further development of HIF2 targeting agents to
see whether they can move the treatment of ccRCC to
the next level, either as monotherapy or in combination
with other novel therapeutics. It is imperative we continue
to strive for a better understanding of how these
agents impact tumor biology and the surrounding microenvironment
to allow us to develop even better treatments
for patients with RCC.
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