Meeting Updates Refine Approaches Toward Renal Cell Carcinoma

Based on new data pertaining to already approved agents and emerging data for novel therapies in the treatment of kidney cancer, a greater understanding of combating advanced tumors is likely to emerge. 

The recent Genitourinary Cancers Symposium held February 13 to 15, 2020, in San Francisco, California, was dominated by new and interesting data from investigators who specialize in treating RCC, each working toward a greater precision approach to systemic therapy selection. “Fortunately, at this point, there are a lot of options, so it has become a really long discussion on what is the best option,” Bradley McGregor, MD, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, both in Boston, Massachusetts, said in an interview withTargeted Therapies in Oncology.

In addition, data from clinical trials of new regimens were presented to audiences eager to hear about monotherapy agents and combinations that eventually could become available to their patients.

Combination and Investigative Therapies

Phase I/II trial data were presented for the small molecule, oral hypoxia-inducible factor (HIF)— 2a inhibitor MK-6482 in advanced clear cell RCC.  In 90% of patients with sporadic clear cell RCC, the Von Hippel-Lindau tumor suppressor protein is defective, which leads to constitutive activation of HIF-2a.1 Elizabeth Plimack, MD, MS, chief of the Division of Genitourinary Medical Oncology and professor in the Department  of  Hematology/Oncology  at  Fox  Chase Cancer Center in  Philadelphia, Pennsylvania, as well as a coinvestigator of the study, said, “MK-6482 is a compelling agent. It inhibits HIF-2a, the root of the RCC pathogenesis pathway. We are all enthusiastic  to see this move forward in trials.” Data from 55 patients receiving the 120-mg daily dose of MK-6482 in the dose-expansion cohort were reported (NCT02974738). Patients previously  had been treated with VEGF/VEGFR inhibitors (93%), immune checkpoint inhibitors (73%), investigational or  other agents (27%), mTOR inhibitors (22%), or cytokine therapy (13%). Most patients had intermediate-risk disease. At a median  follow-up of 13 months,  39 patients (71%)  had discontinued, 55% due to disease progression.¹

The objective response rate (ORR) in all patients was 24%, and the disease control rate (DCR), which included all patients with a complete response (CR), partial response (PR), or stable disease, was 80%. Tumor shrinkage occurred in 69% of patients. Median duration of response (DOR) was not reached. Median progression-free survival (PFS) was 11.0 months in all patients and 16.5, 11.0, and 6.9 months in those with favorable (n = 5), intermediate (n = 40), and poor risk (n = 10), respectively. 

All patients experienced adverse events (AEs), with 2 on-target toxicities observed: anemia (75%) and hypoxia (26%). Two patients experienced grade 4 AEs, and 4 had grade 5 AEs secondary to progressive disease. Two patients discontinued due to treatment- related hypoxia.¹

A phase III trial of MK-6482 monotherapy versus everolimus (Afinitor) in previously treated metastatic clear cell RCC (NCT04195750) is ongoing.1 PD-1 inhibitors such as nivolumab (Opdivo) and pembrolizumab (Keytruda) are recommended in the National Comprehensive Cancer Network (NCCN) guidelines for certain patients in both the frontline and subsequent settings.²At the meeting, multiple investigators explored combination therapy strategies with the PD-1 inhibitor nivolumab.

Phase I/II results were presented for 40 patients treated with the oral receptor tyrosine kinase inhibitor (TKI) sitravatinib combined with nivolumab for advanced clear cell RCC that had progressed on prior antiangiogenic therapy (NCT03015740). At a median follow-up of 17.7 months, the median overall survival (OS) was not reached, with 30 of 38 evaluable patients still alive. The DCR was 92%, with a confirmed ORR of 39%. Four patients discontinued treatment due to AEs.³

The authors noted that sitravatinib plus nivolumab showed superior efficacy compared with previous trials of nivolumab monotherapy. Based on the data, 120 mg was selected as the recommended dose of sitravatinib to be given with nivolumab in phase II of the study.³

Two studies examined the potential of radiation therapy to synergize with nivolumab immunotherapy in RCC.

In the RADVAX RCC trial of dual checkpoint inhibition plus stereotactic body radiotherapy (SBRT) in metastatic RCC (NCT03065179), patients received SBRT plus 4 cycles of dual blockade with nivolumab plus ipilimumab (Yervoy) in the induction phase, followed by nivolumab maintenance therapy. Prior TKI or cytokine therapy was allowed, but prior immune checkpoint inhibitors were not.⁴

There were 25 patients who received SBRT and at least 1 dose of the immunotherapy combination. The ORR was 56%, which was composed of all PRs, at a median follow-up of 24 months. Median PFS was 8.21 months. Median DOR and OS were not reached. Investigators said that the encouraging findings of this small, single-site study warrant further confirmatory trials.⁴

The phase II NIVES trial (NCT03469713) looked at nivolumab combined with SBRT in patients with metastatic RCC that had progressed after up to 2 prior antiangiogenic therapies. SBRT began 7 days after the first dose of nivolumab, which was given for 6 months and continued as maintenance therapy in patients with a response. Of the 69 patients who received at least 1 dose of nivolumab, 67 also received SBRT.⁵

ORR was 19.0% in the 63 patients who received SBRT and more than 1 dose of nivolumab, with a DCR of 63.5%. Median time to response was 2.8 months, and DOR was 9.7 months. Median PFS was 4.1 months, and median OS was 22.07 months. Grade 3-4 treatment-related AEs occurred in 24.6%  of patients.⁵

The study’s primary end point was ORR. The investigators hypothesized that adding SBRT to nivolumab would produce an ORR of 40% compared with the 25% found with nivolumab monotherapy in a previous study. This hypothesis was not confirmed.⁵

““Considering the baseline characteristics of patients, clear cell histology was found to be correlated with an ORR with statistical significance,” said Cristina Masini, MD, of the Medical Oncology Unit, Clinical Cancer Centre, Azienda Unità Sanitaria Locale di Reggio Emilia—IRCCS in Italy, who presented the data at the meeting. “But [in] this small population, it is difficult to demonstrate and interpret these results.”

At a median of 15 months of follow-up, 78.3% of patients had discontinued therapy; 70.4% of discontinuations were due to disease progression and 13.0% were due to treatment-related toxicity. There were 4 deaths.⁵

Updated results of the phase I/Ib dose-escalation and dose-expansion portions of the IVY trial (NCT02009449) were presented. Patients with pretreated RCC received pegilodecakin, a pegylated, recombinant form of human interleukin-10, as monotherapy (n = 24) or combined with the TKI pazopanib (Votrient; n = 4) or an anti—PD-1 agent—pembrolizumab (n = 9) or nivolumab (n = 29).6

ORR was 43% in patients treated with antiPD-1, 33% in the pazopanib cohort, and 20% in the monotherapy cohort. Median DOR was 19.7 months for monotherapy, 7.4 months for the pazopanib group, and not reached (NR) for the anti—PD-1 cohort. Median OS was  10.9 months for monotherapy and NR for the other cohorts. Median PFS was 1.8 months for monotherapy,  3.7 months  for the pazopanib group, and 13.9 months for the anti–PD-1 cohort. The most common treatment-related AEs were anemia, thrombocytopenia, and fatigue. The investigators concluded that these results establish the agent’s activity and confirmed tolerability for this patient population, with the greatest efficacy seen with pegilodecakin plus a PD-1 inhibitor.⁶

OS results from the CALYPSO trial (NCT02819596) were also presented at the meeting. Patients with metastatic papillary RCC received combination therapy with the anti—PD-L1 monoclonal antibody durvalumab (Imfinzi) and savolitinib, a small moleculeMET-targeted TKI.⁷

At the median follow-up of 14.3 months, ORR was 27% for all patients (N = 41), 25% for those with PD-L1—positive tumors (n = 8), and 40% for those withMET-positive tumors (n = 10). Overall, the median PFS was 4.9 months and median OS was 12.3 months, with similar  results for  the PD-L1—positive  andMET-positive subgroups. The investigators concluded thatMETand PD-L1 expression did not appear to be predictive of response, and they plan to extend the CALYPSO trial to evaluate this treatment combination in  more patients.⁷

“CALYPSO is the first trial in this space to look at the combination of  MET  and  PD-L1 [inhibition].  The rationale is clearly strong. I think the results are encouraging but not groundbreaking,” said Cristina Suarez Rodriguez, MD, of the Department of Medical Oncology at Hospital Vall d’Hebron in Barcelona, Spain. “Durable remissions occur, but I can’t tell you whether that’s because of the PD-L1 therapy, the combination, or MET inhibition.”

McGregor agreed that identifying and using predictive biomarkers could aid treatment decisions. “I don’t think we have anything that is a truly predictive biomarker as of yet,” he commented.

Adjuvant Sunitinib

According to the NCCN Guidelines for kidney cancer, patients with stage III clear cell RCC should undergo radical or partial nephrectomy as primary treatment. For adjuvant therapy, sunitinib (Sutent; a TKI targetingVEGF) now has a category 3 recommendation, recently updated from its prior 2B recommendation, with placement on a clinical trial being the preferred strategy for this population (category 2A).²

In previously reported data from the phase II S-TRAC and  ASSURE  trials,  adjuvant  sunitinib was examined in patients with RCC at high risk of recurrence. In S-TRAC (NCT00375674), patients were assigned post nephrectomy to either sunitinib 50 mg/day (n = 309) or placebo (n = 306). The results showed that median duration of disease-free survival (DFS) was significantly longer with sunitinib (6.8 vs 5.6 years; HR, 0.76; 95% CI, 0.59-0.98;  P= .03).⁸

In ASSURE (NCT00326898), patients with resected local RCC were randomly assigned to sunitinib 50 mg/day (n = 647), sorafenib 400 mg twice daily (n = 649), or placebo (n = 647) for approximately 1 year. There were no significant differences in median DFS, which was 5.8 years with sunitinib (HR, 1.02; 97.5% CI, 0.85-1.23;P= .8038), 6.1 years for sorafenib (HR, 0.97; 97.5% CI, 0.80-1.17;  P= .7184), and 6.6 years for placebo, at a median follow-up of 5.8 years.⁹

A poster presented at the meeting detailed results of a retrospective study of patients whose RCC recurred after treatment with adjuvant sunitinib and who then received targeted therapy, including sunitinib retreatment. The primary objective was to analyze PFS after the first and subsequent lines of therapy for patients who experienced relapse of RCC after adjuvant sunitinib. Secondary objectives included ORR, OS, and outcomes for patients receiving retreatment with sunitinib for metastatic disease.¹⁰

In this multi-institutional study, 34 patients with relapsed RCC were identified as having received adjuvant sunitinib. Of these, 25 patients (73.5%) received systemic therapy after relapse.  Median time to relapse was 20.3 months from diagnosis and 7.5 months from the end of adjuvant sunitinib treatment. At a median follow-up of 23.5 months, all but 1 of the 25 patients had experienced progression on first-line systemic therapy. Median OS was 28.7 months (95% CI, 24.4-33).¹⁰

Systemic therapy included VEGF-targeted therapy in 64% of patients, mTOR inhibition in 24%, and immunotherapy in 12%; 7 patients received retreatment with sunitinib. The ORR among 22 evaluable patients was 20.5%; 1 patient experienced a CR, and 6 had PRs. The median PFS was 12.0 months; median OS, 28.7 months.¹⁰

Outcomes were similar among treatment groups, including in patients who relapsed during (<6 months) or after (>6 months) adjuvant sunitinib. The authors concluded that the findings suggest that targeted therapy may improve PFS and OS in patients with RCC that relapses after adjuvant sunitinib. However, the small size of the patient cohort with sunitinib retreatment limits this small, retrospective study.¹⁰

Role of Cabozantinib Post Immunotherapy

Numerous real-world studies have clarified the utility of the oral, small molecule TKI cabozantinib (Cabometyx), which targetsVEGF,MET, andAXL(TABLE).^11-13Cabozantinib had received FDA approval for advanced RCC on the basis of 2 randomized, active-controlled trials, METEOR and CABOSUN.^14,15The open-label, &nbsp;phase &nbsp;III METEOR &nbsp;trial &nbsp;randomly assigned patients with advanced or metastatic RCC with progression afterVEGFR-targeted therapy to either cabozantinib or the mTOR inhibitor everolimus. Median PFS was significantly longer at 7.4 months with cabozantinib versus 3.8 months with everolimus (HR, 0.58; 95% CI, 0.45-0.75;P<.001) at a minimum follow-up of 11 months.¹⁶The phase II CABOSUN trial compared cabozantinib with sunitinib as initial therapy for patients with intermediate- or poor-risk advanced RCC. Median PFS was 8.6 months for cabozantinib, significantly longer than the PFS of 5.3 months for sunitinib (HR, 0.48; 95% CI, 0.31-0.74;P= .0008) at a median follow-up of 25.0 months.¹⁷

In a retrospective study on the efficacy and dosing patterns of cabozantinib in the first- through fourthline settings for all patients in the International mRCC Database Consortium treated with cabozantinib between 2011 and 2019, results demonstrated that the agent has activity as therapy following frontline immunotherapy agents.¹¹

In total, 413 patients with metastatic RCC received cabozantinib as first- (n = 34), second- (n = 143), third- (n = 142), or fourth-line (n = 94) &nbsp;treatment. ORR for all patients was 27%; 50% required cabozantinib dose reduction, with a median time to dose reduction of 1.2 months.¹¹

Given that the need for TKI dose reduction—a surrogate for toxicity and adequate drug exposure&mdash; has been associated with improved outcome for other agents, the effects of the need for cabozantinib dose reduction on time to treatment failure (TTF) and OS were also analyzed. The rates of dose reductions were similar to those reported in clinical trials. Overall, patients who required dose reduction due to toxicity had a significantly longer TTF (HR, 0.37; 95% CI, 0.20-0.67; &nbsp;P<.01) and OS (HR, 0.46; 95% CI, 0.22-0.98; &nbsp;P=.04) than those who did not.¹¹

Among 23 patients who received prior first-line immunotherapy combinations, including ipilimumab plus nivolumab (n = 5) or combinations of PD-1/ PD-L1 and VEGF inhibitors (n = 18), the ORR post cabozantinib was 22%; TTF, 5.4 months; and median OS, 17.4 months, indicating clinical activity for this group.¹¹

Another poster presented results of a real-world, retrospective study of patients with advanced RCC treated with cabozantinib in the French early access program (CABOREAL; NCT03744585), which included &nbsp;patients who had received &nbsp;at least &nbsp;1 dose of cabozantinib. Two subgroup analyses included patients with &nbsp;bone metastases and those pretreated with nivolumab. Of 410 patients in the study, about 30% had poor prognostic risk, more than 40% had at least 3 prior lines of therapy, and 75% had at least 2 prior lines. Bone metastases were present in 56%. Prior systemic treatment with nivolumab was administered to 50.1%.¹²

Of these 409 patients, 65.3% experienced treatment interruptions, 58.7% had dose modifications, and 15.6% had changes to their dosing schedule. Among the 348 patients who discontinued treatment, the reason was disease progression or AEs in 54.6% and 24.9%, respectively. Of the 275 deaths that occurred, 220 were due to disease progression and 8 were due to serious AEs not related to cabozantinib treatment.¹²

Overall, median OS was 14.4 months (95% CI, 12.4-16.2) and not significantly different between patients with and without bone metastases (13.7 vs 15.5 months; &nbsp;P=.09). Median OS also did not differ&nbsp;Overall, median OS was 14.4 months (95% CI, 12.4-16.2) and not significantly different between patients &nbsp;with and without bone metastases (13.7 &nbsp;vs 15.5 months;&nbsp;P=.09). Median OS also did not differ&nbsp;significantly &nbsp;between patients with and without prior nivolumab treatment (15.4 months vs 13.8 months;P=.57). OS decreased from time of cabozantinib initiation regardless of whether patients had bone metastases or prior nivolumab treatment.¹²

Cabozantinib dose reduction was required daily in 62.3% of patients. The median duration of treatment was 7.6 months for the overall cohort and was the longest, at 9.3 months, in the subgroup previously treated with nivolumab. Of the 306 patients (75.2%) who received cabozantinib in the third line or later, 185 (54.4%) went on to receive subsequent systemic therapy.¹

Another study of retrospective outcome data for 162 patients with metastatic RCC eligible for treatment after progression on immunotherapy agents (PD-1 or PD-L1 inhibitors) included postprogression therapy with cabozantinib in 79 patients (48.0%), everolimus in 11 (6.7%), sunitinib in 6 (3.7%), and other agents in 15 (9.25%).¹³

The median PFS of patients treated post progression was 6.5 months (95% CI, 5.1-7.8). Those receiving cabozantinib had a significantly longer median PFS (7.6 months; 95% CI, 5.2-10.1) compared with patients treated with everolimus (3.2 months; 95% CI, 1.8-4.5) or other drugs (4.3 months; 95% CI, 1.3-7.4;P=.001). The median OS (from the first-line therapy) was 41.1 months (95% CI, 30.4-51.8). AEs of any grade occurred in 74% of treated patients, and 35% of patients had grade 3 or 4 AEs.¹⁷This study&rsquo;s results &nbsp;indicated that after progression on immunotherapy, most patients received subsequent therapy with VEGF TKIs and mTOR inhibitors, which were shown to be &nbsp;active &nbsp;and &nbsp;safe; &nbsp;of &nbsp;these, &nbsp;cabozantinib was associated with the longest PFS.¹³

Making the Treatment Decision

When asked how to make a treatment decision, given multiple options, McGregor said, &ldquo;I think at the end of the day, this comes down to shared decision making with the patient and the physician.&rdquo;

More data will be needed to establish the role of each agent in the sequence of therapy, but investigators said they are &nbsp;optimistic that knowledge of biomarkers and patient characteristics can help elucidate the role of each of these systemic therapies.

References

1. Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II study of the oral HIF-2 a inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). JClin Oncol. 2020;38(suppl 6; abstr 611). doi: 10.1200/JCO.2020.38.6_suppl.611.
2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology.Kidney Cancer(version 2.2020). bit.ly/33o3sel. Accessed March 12, 2020.
3. Msaouel P, Thall PF, Yuan Y, et al. A phase I/II trial of sitravatinib (sitra) combined with nivolumab (nivo) in patients (pts) with advanced clear cell renal cell cancer (aCCRCC) that progressed on prior VEGF-targeted therapy. &nbsp;J Clin Oncol. 2020;38(suppl 6; abstr 612). doi: 10.1200/ JCO.2020.38.6_suppl.612.
4. Hammers HJ, Vonmerveldt D, Ahn C, et al. Combination of dual immune checkpoint inhibition (ICI) with stereotactic radiation (SBRT) in metastatic renal cell carcinoma (mRCC) (RADVAX RCC). &nbsp;J Clin Oncol. 2020;38(suppl 6; abstr 614). doi: 10.1200/JCO.2020.38.6_suppl.614.
5. Masini C, Iotti C, De Giorgi U, et al. Nivolumab (NIVO) in combination with stereotactic &nbsp;body radiotherapy (SBRT) in &nbsp;pretreated &nbsp;patients (pts) with metastatic renal cell carcinoma (mRCC): first results of phase II NIVES study. &nbsp;J Clin Oncol. 2020;38(suppl 6; abstr 613). doi: 10.1200/JCO.2020.38.6_suppl.613.
6. Naing A, Papadopoulos KP, Wong DJL, et al. Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma (RCC): updated results from phase I/Ib IVY study.J Clin Oncol. 2020;38(suppl 6; &nbsp;abstr &nbsp;679). &nbsp;doi: &nbsp;10.1200/JCO.2020.38.6_suppl.679.
7. Suarez Rodriguez C, Larkin JMG, Patel P, et al. Overall survival results for durvalumab and savolitinib in metastatic papillary renal cancer.J Clin Oncol. 2020;38(suppl 6; abstr 619). doi: 10.1200/ JCO.2020.38.6_suppl.619.
8. Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy.N Engl J Med. 2016;375(23):2246-2254. doi: 10.1056/NEJMoa1611406.
9. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.Lancet.2016;387(10032):2008-2016. doi: 10.1016/S01406736(16)00559-6
10. de Velasco G, Ruiz-Granados &Aacute;, Reig O, et al. Outcomes of systemic therapy in relapsed renal cell carcinoma (RCC) treated with adjuvant sunitinib (AS).J Clin Oncol. 2020;38(suppl 6; abstr 701). doi: 10.1200/JCO.2020.38.6_suppl.701.
11. Gan CL, Dudani S, Wells C, et al. Cabozantinib real-world effectiveness in the first through fourth-line settings for the treatment of metastatic renal cell carcinoma (mRCC): results from the International mRCC Database Consortium (IMDC).J Clin Oncol. 2020;38(suppl 6; abstr 639). doi: 10.1200/JCO.2020.38.6_suppl.639.
12. Gross-Goupil M, Flechon A, Chevreau C, &nbsp;et &nbsp;al. &nbsp;Real-world &nbsp;data of cabozantinib in patients with VEGF-refractory metastatic renal cell carcinoma (mRCC): results from the French Early Access Program (CABOREAL). &nbsp;J Clin Oncol. 2020;38(suppl 6; abstr 683). doi: 10.1200/ JCO.2020.38.6_suppl.683
13. Santini D, Stellato M, De Giorgi U, et al. Clinical outcomes of metastatic renal carcinoma following disease progression to programmed death (PD)-1 or PD-L1 inhibitors (I-O): a Meet-URO group real-world study (Meet-Uro 7).J Clin Oncol. 2020;38(suppl 6; abstr 691). doi: 10.1200/JCO.2020.38.6_suppl.691.
14. Exelis announces FDA approval of Cabometyx (cabozantinib) tablets for patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy [news release]. South San Francisco, CA: Exelis, &nbsp;Inc; April &nbsp;25, &nbsp;2016. bit.ly/33gAiNW. &nbsp;Accessed &nbsp;March &nbsp;13, &nbsp;2020.
15. FDA grants regular approval to Cabometyx for first-line treatment of advanced renal cell carcinoma. FDA website. bit.ly/2Wzocyd. Published December 19, 2017. Accessed March 13, 2020.
16. Choueiri TK, &nbsp;Escudier &nbsp;B, &nbsp;Powles &nbsp;T, &nbsp;et &nbsp;al; &nbsp;METEOR &nbsp;Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. &nbsp;N Engl J Med.2015;373(19):1814-1823. doi: 10.1056/NEJMoa1510016.
17. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update.Eur J &nbsp;Cancer. 2018;94:115-125. doi: 10.1016/j. ejca.2018.02.012.