Essential Peer-Reviewed Reading in Kidney Cancer
The peer-reviewed articles summarized in this section were selected by the
Editor-in-Chief, Robert A. Figlin, MD, for their timeliness, importance, relevance,
and potential impact on clinical practice or translational research.
IImaging of tumour response to immunotherapy.
Dromain C,Beigelman C, Pozzessere C, et al. Eur Radiol
Exp. 2020 Jan 3;4(1):2. doi: 10.1186/s41747-019-0134-1.
Summary: The novel mechanism of action of immune
checkpoint inhibitors (CPIs), with immune and T cell activation,
leads to unusual patterns of response on imaging,
with the advent of so-called pseudoprogression
being more pronounced and frequently observed when
compared to other anticancer therapies. Pseudoprogression,
described in about 2-10% of patients treated with
ICIs, corresponds to an increase of tumour burden
and/or the appearance of new lesions due to infiltration
by activated T cells before the disease responds to therapy.
To overcome the limitation of response evaluation
criteria in solid tumors (RECIST) to assess these specific
changes, new imaging criteria-so-called immune-related
response criteria and then immune-related RECIST (ir-
RECIST)-were proposed. The major modification involved
the inclusion of the measurements of new target
lesions into disease assessments and the need for a 4-
week re-assessment to confirm or not confirm progression.
The RECIST working group introduced the new
concept of “unconfirmed progression”, into the ir-
RECIST.
Conclusion: This paper reviews current immunotherapeutic
approaches and summarizes radiologic criteria to
evaluate new patterns of response to immunotherapy.
Furthermore, imaging features of immunotherapy-related
adverse events and available predictive biomarkers
of response are presented.
NCI 6896: a phase I trial of vorinostat (SAHA) and
isotretinoin (13-cis retinoic acid) in the treatment of
patients with advanced renal cell carcinoma. Molina
AM, van der Mijn C, Christos P, et al. Invest New Drugs.
2020 Jan 3. doi: 10.1007/s10637-019-00880-7. Epub
ahead of print
Summary: Preclinical studies suggest that histone
deacetylase (HDAC) inhibitors may restore tumor sensitivity
to retinoids and have synergistic anti-tumor activity
when combined. This Phase I clinical trial evaluated
the safety and preliminary efficacy of combining the
oral HDAC inhibitor vorinostat and isotretinoin in patients
with advanced renal cell carcinoma (RCC).
Vorinostat was administered at 300 mg orally twice daily
in combination with escalating doses Vorinostat was administered
at 300 mg orally twice daily in combination
with escalating doses of isotretinoin in patients with advanced
RCC. of isotretinoin for 3 consecutive days per
week. A standard 3 + 3 dose escalation design was used.
Dose limiting toxicities (DLT) were assessed during the
first cycle to determine the maximum tolerated dose
(MTD). Fourteen patients enrolled on the trial of which
4 Kidney Cancer Journal
12 were evaluable for toxicity (6 cohort 1; 3 cohort 2; 3
cohort 3) and 11 for tumor response. One patient in cohort
1 experienced a DLT (grade 3 depression). Common
grade 1-2 toxicities included fatigue and GI effects (nausea,
diarrhea, anorexia). MTD was established as vorinostat
300 mg with isoretinoin 0.5 mg/kg twice daily 3 days
per week. Best responses in evaluable patients included 1
partial response and 9 stable disease, lasting a median of
3.7 months (range 1.8 10.4 months).
Conclusion: The combination of vorinostat and
isotretinoin is safe, tolerable and associated with responses
in patients with refractory metastatic RCC.
Outcomes based on age in the phase III METEOR trial
of cabozantinib versus everolimus in patients with
advanced renal cell carcinoma. Donskov F, Motzer RJ,
Voog E, et al. Eur Cancer. 2019 Dec 27;126:1-10. doi:
10.1016/j.ejca.2019.10.032. Epub ahead of print
Summary: Cabozantinib improved progression-free survival
(PFS), overall survival (OS) and objective response
rate (ORR) compared with everolimus in patients with
advanced RCC after prior antiangiogenic therapy in the
phase III METEOR trial (NCT01865747). Limited data are
available on the use of targeted therapies in older patients
with advanced RCC. Efficacy and safety in METEOR
were retrospectively analyzed for three age
subgroups: <65 (n = 394), 65-74 (n = 201) and 75 years
(n = 63). PFS, OS and ORR were improved with cabozantinib
compared with everolimus in all age subgroups.
The PFS hazard ratios (HRs) were 0.53 (95% confidence
interval CI: 0.41-0.68), 0.53 (95% CI: 0.37-0.77) and
0.38 (95% CI: 0.18-0.79) for <65, 65-74 and 75 years,
respectively, and the OS HRs were 0.72 (95% CI: 0.54-
0.95), 0.66 (95% CI: 0.44-0.99) and 0.57 (95% CI: 0.28-
1.14). The ORR for cabozantinib versus everolimus was
15% vs 5%, 21% vs 2% and 19% vs 0%, respectively. No
significant differences were observed in PFS or OS with
age as a categorical or continuous variable. Grade III/IV
adverse events (AEs) were generally consistent across
subgroups, although fatigue, hypertension and hyponatremia
occurred more frequently in older patients
treated with cabozantinib. Dose reductions to manage
AEs were more frequent in patients receiving cabozantinib
than in those receiving everolimus. Dose reductions
and treatment discontinuation due to AEs were more
frequent in older patients in both treatment groups.
Conclusion: Cabozantinib improved PFS, OS and ORR
compared with everolimus in previously treated patients
with advanced RCC, irrespective of age group, supporting
use in all age categories. Proactive dose modification
and supportive care may help to mitigate AEs in older
patients while maintaining efficacy.
J O U R N A L C L U B
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