Basics
What are the histologic subtypes of RCC?
* Clear cell (75% incidence--usually associated with VHL mutation).
* Papillary--High grade
* Papillary--Low grade
* Chromophobe (5% incidence--associated with FLCN mutation)
Ipilimumab Mechanism of action and any 2 side effects?
Ipilimumab is a monoclonal antibody that targets CTLA-4 (cytotoxic T-lymphocyte–associated antigen 4), a checkpoint receptor on T cells.
Immune mediated endocrinopathies, hepatitis, colitis, nephritis and renal dysfunction, encephalitis.
Monitor clinical chemistries, ACTH level, and thyroid function tests prior to each dose.
Treatment for non- metastatic disease [Stage 1/2/3]
1) Nephrectomy
2) Adjuvant Pembrolizumab for high-risk.
60 year old otherwise healthy female with 7.5 cm clear cell RCC, nuclear grade 4, with extracapsular extension, and 5/7 lymph nodes positive. How will you treat?
Adjuvant pembrolizumab
Name any 1 Hereditary RCC syndrome?
--> von Hippel-Lindau Disease[Hemangioblastomas Clear cell RCC, pheochromocytomas, pancreatic neuroendocrine tumors and cysts]
--> Tuberous Sclerosis[CNS Tumors, Angiomyolipomas of the kidney Clear cell RCC ]
--> Hereditary Papillary RCC
cabozantinib -- Mechanism of action and toxicities (any 2)?
Mechanism of Action: Multikinase inhibitor targeting:VEGFR, MET, AXL, RET, KIT, FLT3, and others
→ Inhibits angiogenesis, tumor growth, metastasis, and drug resistance mechanisms.
The most common (≥ 25%) adverse reactions are: diarrhea, fatigue, decreased appetite, palmar-plantar erythrodysesthesia (PPE), nausea, hypertension, and vomiting.
Warnings- • Hemorrhage, Perforations and Fistulas, Thrombotic Events, Hypertension and Hypertensive Crisis, Diarrhea, Proteinuria, Osteonecrosis of the jaw[Withhold CABOMETYX for at least 28 days prior to invasive dental procedures and for development of ONJ], Wound complications [Withhold CABOMETYX for dehiscence or complications requiring medical intervention]
Which patients with non-metastatic RCC are considered high-risk and likely to benefit from adjuvant pembrolizumab?
Adjuvant pembrolizumab (anti-PD-1 immunotherapy) is the preferred option for eligible patients with high-risk clear cell RCC after complete resection.
The choice of adjuvant pembrolizumab 200 mgQ3 weeks~1 year(<=17 cycles) is based on the KEYNOTE-564 trial, which demonstrated improved disease-free survival and overall survival in this population.
Intermediate-risk features typically include:
--> pT2, grade 4 or sarcomatoid features, N0
-->pT3, any grade, N0
High risk of recurrence:
--> pT4, any grade, N0
--> Any pT, any grade, N+
M1 NED Metastatectomy within 1 year of nephrectomy were also included in the trial. {NED = No Evidence of Disease}
The patients were ECOG PS 0-1.
True or false?
IO TKI regimens will have a higher probability of upfront response as compared to IO-IO regimens.
True!
RCC Staging?
Non-Metastatic
Stage 1--> T1N0M0---> <7 cm, confined.
Stage II--> T2N0M0---> > 7 cm, confined
Stage III--> T1-2, N1 or T3, N0-1
TIIIa--> extracapsular extension or renal vein.
TIIIb --> Renal vein below the diaphragm.
TIIIC--> Renal vein above the diaphragm or invading vein wall.
N1 --> regional nodes involved.
Metastatic disease/ invasion beyond gerota's fascia
Stage IV--> T4(any N or M) or M1 {T4 is extension beyond gerota's fascia}
Belzutifan- Mechanism of action? toxicites
--> Belzutifan is an oral HIF-2α (hypoxia-inducible factor 2 alpha) inhibitor
--> Approval for treatment of adult patients with advanced renal cell carcinoma (RCC) following a PD-1/ PD-L1 and VEGF-TKI.
--> Most common (≥25%) adverse reactions: anemia, lymphocytopenia, fatigue, musculoskeletal pain, increased creatinine, elevated liver enzymes, hyponatremia, hyperkalaemia
--> Hypoxia: Monitor oxygen saturation before initiation of, and periodically throughout, treatment with belzutifan.
First-line therapy for relapse or stage IV disease?
Both favorable and poor/intermediate groups:
IO TKI regimens
--> Axitinib+pembrolizumab
--> Cabozantinib+nivolumab
--> Lenvantanib+pembrolizumab
IO IO regimen
--> ipilimumab + nivolumab
------------------
--> For poor/intermediate, we also have Cabozantinib alone for patients who didn't tolerate IO therapy.
True or false
Ipi+nivo is not a highly powerful regimen for patients with extensive bone mets?
Ipi+ nivo has a more durable response as compared to IO-TKI regimens?
True!
True!
IMDC prognostic score?
Factors-->
1) KPS<80
2) Dx to treatment less than 1 year
3) Anemia
4) Leukocytosis
5) Thrombocytosis
6) Hypercalcemia
Favourable--0 factors [mOS 37 months~ 3years, 1 month]
Intermediate--1-2 factors [mOS 27 months ~ 2 years, 3 months]
Poor-- 3-6 factors [mOS 8.8 months]
Checkmate 214 study?
Treatment-naive metastatic clear cell RCC
Arm A Arm B
Nivo +Ipi Sunitinib
Q 3W x 4 doses, then nivo alone
Q2 weeks--treatment until progression or
unacceptable toxicity.
Results-----> Favorable group--> Similar OS, PFS favoured sunitinib.
Poor and intermediate group--> Improved OS and PFS with nivo + ipi.
Subsequent therapy for clear cell RCC for relapse or stage IV disease in patients who are IO therapy naive? Name any four regimens.
If they are IO naive---Give IO
--> Ipi nivo
--> Axi Pem
--> Len Pem
--> Cabo Nivo
--> Everolimus + Lenvatinib
--> Nivo alone
--> Cabo alone
True or False?
In favourable risk individuals trial comparing IO-IO [Ipi+Nivo] and sunitinib showed similar overall survival, but sunitinib had better progression-free survival.
True.
In the favorable-risk subgroup of CheckMate‑214 (ipilimumab + nivolumab vs sunitinib):
Overall Survival was similar between the two groups — no statistically significant difference.
Progression‑Free Survival actually favored sunitinib, with better median PFS compared to the IO‑IO arm.
To restate: in favorable-risk patients, Ipi + Nivo did not outperform sunitinib in OS and had inferior PFS, so sunitinib showed better PFS.
Name a cancer Prediction tool that provides a numerical estimate of the probability of disease-free and overall survival in patients with RCC?
ASSURE RCC Prognostic Nomogram.
It provides an estimate of disease-free and overall survival probabilities, helping guide discussions with patients about their absolute risk and the potential risk reduction.
KEYNOTE-426 Trial?
Pembro + Axi vs Sunitinib
Fav group--> similar OS, PFS favoured the combination.
Unfav group--> Both OS and PFS favoured combination.
Subsequent therapy for clear cell RCC for relapse or stage IV disease in patients who have been exposed to IO therapy? Name any four regimens.
--> Cabozantinib
--> Axitinib
--> Belzutifan [hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor]
--> Everolimus + Lenvatinib
True-false?
1) IO-IO and IO-TKI regimens have OS and PFS benefits in the poor and intermediate-poor risk groups.
2) IO-TKI regimens have no OS benefit but PFS benefit in the favourable group.
1) True
2) True