Senthil Kumar: First-Line Therapy in RCC, Expanding Choices in a New Era

Senthil Kumar, Medical Oncologist at Red Hills, Chennai, posted on X:

“First-Line Therapy in RCC: Expanding Choices in a New Era.

CheckMate 214: Nivolumab and Ipilimumab.

Dosing:

Nivolumab: 3 mg/kg IV every 2 weeks

Ipilimumab: 1 mg/kg IV every 3 weeks (4 doses)

Comparator Arm: Sunitinib, 50 mg oral daily (4 weeks on, 2 weeks off)

Updated Outcomes (8-Year Data):

Overall Survival (OS): 52.7 vs. 37.8 months.

Progression-Free Survival (PFS): 12.4 vs. 12.3 months (note: OS benefit , no PFS benefit, often the case with i/o).

Duration of Response (DoR): 76.2 vs. 25.1 months.

Complete Response (CR): ~12% across all risk groups.

Key Points:

Durable responses with sustained benefit.

May produce faster responses, esp in aggressive tumors.

An I/O + I/O doublet may also be used as a second-line therapy after a first-line I/O-TKI combination.

Higher toxicity burden: 56% grade 3/4 adverse events and 30% discontinuation rates.

CheckMate 9ER: Nivolumab and Cabozantinib.

Dosing:

Nivolumab: 240 mg IV every 2 weeks or 480 mg every 4 weeks

Cabozantinib: 40 mg oral daily

Updated Outcomes:

Median OS: 47 vs. 36 months.

Progression-Free Survival (PFS): 16 vs. 8 months.

Particularly effective in bone metastases subsets.

Key Points:

Cabozantinib was used at a lower dose (40 mg) though

KEYNOTE-426: Pembrolizumab and Axitinib.

Dosing:

Pembrolizumab: 200 mg IV every 3 weeks

Axitinib: 5 mg oral twice daily

Updated Outcomes:

OS: 47.2 months.

PFS: 15.7 months (ESMO 2023).

Key Points:

Most tolerable combination with fewer grade 3/4 adverse events.

CLEAR Study: Lenvatinib and Pembrolizumab.

Dosing:

Lenvatinib: 20 mg oral daily

Pembrolizumab: 200 mg IV every 3 weeks

Updated Outcomes:

OS: 53.7 months (ESMO 2023).

Key Points:

Exceptional PFS and ORR results, with sustained survival benefit.

Particularly effective in aggressive or symptomatic tumors.

JAVELIN Renal 101: Avelumab and Axitinib.

Dosing:

Avelumab: 800 mg IV every 2 weeks

Axitinib: 5 mg oral twice daily

Updated Outcomes:

Median OS: 45 vs. 39 months.

Median PFS: 14 vs. 9 months.

COSMIC-313: Triplet Therapy (Cabozantinib, Nivolumab and Ipilimumab).

Dosing:

Cabozantinib: 40 mg oral daily

Nivolumab: 3 mg/kg IV every 3 weeks

Ipilimumab: 1 mg/kg IV every 3 weeks (4 doses)

Updated Outcomes:

Progression-Free Survival (PFS): 17.0 vs. 8.3 months.

Key Points:

The combination targets VEGF, PD1, and CTLA4 pathways, enhancing efficacy in intermediate-/poor-risk patients.

However, the toxicity is very high, with frequent grade 3/4 adverse events and higher discontinuation rates compared to other combinations.

Should be reserved for selected patients who can tolerate aggressive therapy and may benefit from triple pathway inhibition.

Comparing I/O + I/O and I/O + TKI

1. Response Rates:

I/O + TKI (e.g., Nivolumab + Cabozantinib, Lenvatinib + Pembrolizumab) show 10-20% higher ORR than I/O + I/O (e.g., Nivolumab + Ipilimumab).

I/O + I/O may provide faster responses for aggressive tumors.

2. Toxicity Profile:

Most tolerable: Pembrolizumab + Axitinib.

Least tolerable: Nivolumab + Ipilimumab (56% grade 3/4 AEs, 30% discontinuation rates).

Triplet therapy has the highest toxicity burden, requiring careful patient selection.

3. Affordability:

TKI combinations are generally more cost-effective than I/O + I/O or triplet regimens.

4. Sustained Benefit:

Immunotherapy regimens (I/O + I/O or I/O + TKI) show sustained duration of response and prolonged PFS compared to TKIs alone.

Key Insights for Clinical Decision-Making

Favorable-Risk Patients:

An informed decision may be made on TKI vs. I/O + I/O vs. I/O + TKI based on affordability, tumor volume, aggressiveness, site of metastases, fitness, and toxicity profile.

Intermediate-/Poor-Risk Patients:

I/O + TKI combinations like Nivolumab and Cabozantinib or Pembrolizumab and Lenvatinib are highly effective, especially for aggressive disease or bone metastasis.”