Immunotherapy Sequencing Must Be Personalized During Therapy Selection for Metastatic RCC

Although immuno-oncology (IO) doublet regimens continue to dominate the standard of care (SOC) for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC), the phase 3 PDIGREE/Alliance A031704 trial (NCT03793166) could help inform immunotherapy sequencing and adaptation before radiographic progression, according to Alan Tan, MD.

Of note, the adaptive trial included patients with metastatic ccRCC who had not received prior systemic therapy and had intermediate/poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium.1 Step 1 of the study included induction, in which patients were treated with ipilimumab (Yervoy) at a dosing level of 1 mg/kg plus nivolumab (Opdivo) at 3 mg/kg every 3 weeks for up to 4 cycles. Step 2 of the study was adapted for response. After 3 months, patients with a complete response (CR) received nivolumab at 480 mg every 4 weeks. Patients who had disease progression received cabozantinib (Cabometyx) at 60 mg daily. However, if patients did not achieve a CR or had disease progression, they were treated with 480 mg of nivolumab every 4 weeks or nivolumab at the same dose level plus cabozantinib at 40 mg daily.

“The ultimate significance is that we should be mindful of who we select for dual IO vs IO/TKI [therapy],” Tan emphasized during an interview with OncLive®. “We’ve come a long way with all these IO combinations, and [now we need to gain] experience with the combinations and select [patients who are] most appropriate [to receive] IO/IO [vs] who’s more appropriate [to receive IO/TKI] to try to rescue them from clinical deterioration or primary progressive disease [PD].”

In the interview, Tan discussed the rationale of the PDIGREE study, key results from the step 1 analysis, and future directions for research.

Tan is an associate professor of medicine in the Division of Hematology Oncology in the Department of Medicine at Vanderbilt University Medical Center in Nashville, Tennessee.

OncLive: What was the rationale for the PDIGREE trial?

Tan: This trial was thought of over a decade ago, so the paradigm has dramatically shifted since then, with IO combinations becoming the SOC as recently as 2018. However, the rationale [for PDIGREE] was having an IO doublet as first-line therapy. Is there an adaptive type of strategy where we can maybe de-escalate patients who are already having CRs, and maybe intensify [treatment for] patients who don’t have a CR and have a partial response [PR]? [This trial used] an adaptive approach based on RECIST responses and looked to see whether intensification with nivolumab plus cabozantinib as an adaptive approach to intensify in subsequent [lines of] therapy could improve outcomes.

What was the study design and the methodology used?

[In] the CheckMate 214 study [NCT02231749], which is a large phase 3 study that reported a 9-year follow-up [in June 2025], 31% of patients were still alive in that study [who were treated with nivolumab plus ipilimumab].2 This is the benchmark currently for frontline therapy with an IO/IO combination. PDIGREE used the frontline induction period of ipilimumab plus nivolumab for 4 cycles.1 Based on responses, we had these patients [receive] nivolumab if they had CRs. If they had PRs or stable disease, they would [be randomly assigned] to [receive] cabozantinib plus nivolumab vs nivolumab [alone]. If patients had PD, they would receive single-agent cabozantinib. [This design is] not far-fetched from what we’re doing currently. The only major difference, based on recent evidence, is that we are not doing IO after IO, based on findings from the [phase 3] TiNivo-2 [NCT04987203] and CONTACT-03 [NCT04338269] trials.

What were the key results from the step 1 analysis of PDIGREE?

This was a major effort; this is probably the largest frontline cooperative group study ever done. We enrolled 1111 patients in this study across over 500 academic centers. We have not met our primary end point [of OS] yet. After the first 3 months of induction treatment with ipilimumab and nivolumab, what we learned is that this is a different type of population than [that enrolled in] the CheckMate 214 study, even though the inclusion and exclusion criteria were relatively similar. However, 48.6% of the sites were community sites; therefore, there was probably a mixed bag of worse performers, more poor-risk patients, and patients who already had a high burden of disease and poor performance status [at baseline].

There were grade 5 events that we would have normally seen in the CheckMate 214 study, but we also had deaths due to disease progression. The take-home point here is that we should be cognizant of who we select for upfront IO/IO. [All patients] want to have that durable CR we saw in in CheckMate 214 and have a [potential] chance to stop therapy. Nevertheless, we have to be careful of who we select for that, because if we make the wrong choice and put all our eggs into the IO-only basket, we may risk [the lives of] these [patients who progress early and die within 3 months. Thirty-seven patients died on the study in the first 3 months of the induction period. Patients who are at higher risk with deteriorating clinical status should likely start with an IO/TKI combination, such as nivolumab/cabozantinib, pembrolizumab [Keytruda]/axitinib [Inlyta], or lenvatinib [Lenvima]/pembrolizumab.

What were the notable safety data?

When you add a CTLA-4–directed agent to a PD-1 inhibitor, [there is a] higher incidence of grade 3/4 [adverse effects (AEs)], and these include autoimmune colitis, autoimmune endocrinopathies, pneumonitis, and so forth. The incidence of these severe AEs has not strikingly increased from what we saw in CheckMate 214.

What are some future directions for research?

We don’t know when we’re going to reach the primary end point [of PDIGREE]. Once we hit that end point, we’re going to learn a lot more about whether this adaptive approach is appropriate. [We’ll also identify whether] we should intensify with IO/TKI therapy after ipilimumab/nivolumab and whether this is feasible. There are some biases based on CONTACT-03 and TiNivo-2 [data suggesting] that we shouldn’t continue [IO/TKI therapy] after IO, but it remains to be seen based on this adaptive type of strategy. We’re also going to learn about more biomarkers in the distant future. We have specimen collection throughout the whole protocol and are looking at exciting biomarkers like KIM-1, circulating tumor DNA, and other RNA signatures.

References

1. Zhang T, Ballman KV, McGregor BA, et al. Ipilimumab and nivolumab in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated on the phase 3 PDIGREE (Alliance A031704) trial: results from step 1 analysis. J Clin Oncol. 2025;43(suppl 16):4516. doi:10.1200/JCO.2025.43.16_suppl.451
2. Choueiri TK, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: final analysis from the phase 3 CheckMate 214 trial. J Clin Oncol. 2025;43(suppl 16):4505. doi:10.1200/JCO.2025.43.16_suppl.4505