Combination Therapies Approaching the Advanced RCC Treatment Paradigm

Although few combination regimens have yet made their way into the paradigm for RCC, 4 combinations have generated interest among genitourinary oncologists, including 2 that received a Breakthrough Therapy designation from the FDA, and another that was granted a priority review.

Each of the combinations approaching addition to the treatment paradigm for patients with RCC incorporates immunotherapy, demonstrating the growing role of this modality. Single-agent nivolumab (Opdivo), a PD-1 inhibitor, has already been included in National Comprehensive Cancer Network (NCCN) guidelines as a preferred agent for patients with previously treated advanced clear cell RCC (TABLE 1).¹

Mayer Fishman, MD, PhD, a medical oncologist specializing in genitourinary oncology at Moffitt Cancer Center in Tampa, Florida, sees these developments as positive for both patients and physicians. “Going forward, we’ll still see the VEGF monotherapy model for low-risk patients due to its oral-only, outpatient nature and strong response rate,” he told Targeted Therapies in OncologyTM. “But we can expect these emerging combinations to become the dominant practice patterns for patients with intermediate- and poor-risk disease, including patients with PD-L1 positivity.”

Here’s a look at where these combination therapies stand, what is understood about the science behind them, and how they might benefit patients in the future.

NIVOLUMAB + IPILIMUMAB

At the European Society for Medical Oncology (ESMO) 2017 Congress, much attention was focused on Bernard Escudier, MD’s presentation of results from the phase III CheckMate 214 study of the combination of nivolumab and ipilimumab (Yervoy), a CTLA-4 inhibitor, versus sunitinib (Sutent) for patients with treatment-naïve metastatic RCC.²The multitargeted receptor tyrosine kinase inhibitor sunitinib is currently the rst-line standard-of-care treatment for patients with advanced RCC.

In the trial, nearly 1100 patients were randomized to receive either 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 week, or 50-mg oral sunitinib daily for 4 weeks in 6-week cycles. The primary endpoints were objective response rate (ORR), progression-free survival (PFS) per independent committee, and overall survival (OS). Efficacy was also evaluated by IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) risk group and PD-L1 expression.

In patients with intermediate/high-risk metastatic RCC, the combination regimen showed an ORR of 41.6% compared with 26.5% in those treated with sunitinib (P <.0001). Of these responses, 9.4% of patients achieved a complete response (CR) on the combination regimen while only 1.2% did on sunitinib. The median duration of response was signi cantly superior with nivolumab and ipilimumab compared with sunitinib (not reached vs 18.2 months).

PFS and OS also improved with the combination in patients with intermediate- and poor-risk disease; this group made up approximately 75.0% of the intention-to-treat (ITT) population. The PFS in these patients was 11.6 months with the combination versus 8.4 months with sunitinib (HR, 0.82; 99.1% CI, 0.64-1.05; P = .0331), although this did not achieve signi cance.

The median OS was not reached with the combi- nation compared with 26.0 months with sunitinib therapy (HR, 0.63; 99.8% CI, 0.44-0.89; P <.0001).

Escudier, from Institut Gustave Roussy, Villejuif, France, reported fewer serious adverse events (AEs) in the combination therapy group, where 46% of patients experienced grade 3-5 treatment-related AEs compared with 63% in the sunitinib arm. &ldquo;More high- grade treatment-related AEs were observed with suni- tinib, and patients reported better symptom control with nivolumab and ipilimumab versus sunitinib,&rdquo; said Escudier during the presentation at ESMO.

The most common AEs in the immunotherapy arm were fatigue and pruritus; 60% of this group required steroids to manage immune-related AEs.

Seven treatment-related deaths were ascribed to the combination regimen versus 4 patients treated with sunitinib. Investigators reported no significant differences between treatment arms in terms of quality-of-life factors.

Based on what he called this &ldquo;manageable&rdquo; safety profile, Escudier told attendees that CheckMate 214&rsquo;s results support the use of nivolumab plus ipilimumab as a new standard of care in metastatic RCC, at least in intermediate- and poor-risk patients.

The FDA granted a priority review for the combination as a frontline treatment for patients with advanced RCC who have intermediate- or poor-risk disease. The FDA&rsquo;s decision on the approval of the combination is expected within 6 months of receiving the priority review designation, by April 16, 2018.

Fishman sees merit in this approach. &ldquo;There&rsquo;s been so much interest in nivolumab recently that, practically speaking, almost every [patient with] renal cell carci- noma has been anticipated to be placed on nivolumab at some point,&rdquo; he added.

The FDA has approved nivolumab for the treatment of patients with previously treated metastatic RCC, but it is not yet approved as a rst-line treatment in this setting.

ATEZOLIZUMAB + BEVACIZUMAB

The combination of the anti—PD-L1 agent atezolizumab (Tecentriq) with bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody, first showed promise in the phase II IMmotion 150 trial, which was also presented at ESMO 2017. The combination showed a clinically meaningful PFS bene t compared with sunitinib in patients with untreated metastatic RCC.³Additionally, the safety was combination was found

to be manageable and consistent with the toxicity pro le of each single agent.

Findings of the study were confirmed in the phase III IMmotion 151 study when data were presented at the 2018 Genitourinary Cancers Symposium. The IMmotion 151 study compared the frontline combination of atezolizumab and bevacizumab with sunitinib in patients with PD-L1—positive metastatic RCC.⁴

Robert J. Motzer, MD, reported at the symposium that the first-line combination of atezolizumab and bevacizumab reduces the likelihood of disease progression better than sunitinib (see page 34 for further analysis from the study). He noted that patients with PD-L1—positive tumors appear to benefit more than other patients.

IMmotion 151 enrolled 915 patients with RCC; of these, 362 were PD-L1—positive. Primary endpoints included PFS in PD-L1&ndash;positive patients and OS in an ITT analysis.

Motzer noted that after a median survival follow-up of 15 months, the PFS was 11.2 months for the combined regimen in the ITT group compared with 8.4 months for the sunitinib arm. In the PD-L1—positive group, the combined-regimen group experienced a median PFS of 11.2 months compared with 7.7 months for PD-L1&ndash;positive patients in the sunitinib arm.

Twelve percent of patients discontinued treatment with the combination due to AEs compared with 8% in the sunitinib arm. Sixteen percent of patients in the combination arm required concomitant treatment with corticosteroids for immune-related AEs, which is lower than in studies for other immunotherapy combinations, Motzer noted.

Regarding the risk of disease progression in the overall study population, Motzer reported that patients on the combined regimen saw their risk decrease by 17% compared with patients in the sunitinib arm (HR, 0.83; 95% CI, 0.70-0.97; P = .0219). Risk of progression decreased by 26.0% for PD-L1—positive patients who took atezolizumab plus bevacizumab compared with those who took sunitinib (HR, 0.74; 95% CI, 0.57- 0.96; P = .0217).

An independent review committee (IRC) of PFS demonstrated slightly different ndings in PD-L1— positive patients. The median PFS was 8.9 months (95% CI, 6.9-12.5) for the combination compared with 7.2 months for sunitinib (95% CI, 6.1-11.1) in the IRC assessment (TABLE 2).

Motzer told colleagues that survival outcomes will be analyzed when data mature. The current ndings support consideration of atezolizumab plus bevaci- zumab as a rst-line treatment option for patients with PD-L1—positive advanced RCC, he said.

ASCO expert Sumanta K. Pal, MD, said that the study was an important breakthrough and that the improved survival with the combination, along with the mild toxicity pro le, demonstrated in the study suggested that atezolizumab and bevacizumab could become a standard frontline treatment for select patients with metastatic RCC, during a press briefing at the Genitourinary Cancers Symposium.

Findings from the IMmotion 151 study are likely to be submitted to the FDA for a potential approval.

AXITINIB + AVELUMAB

Next is the PD-L1 inhibitor avelumab (Bavencio) paired with the VEGF inhibitor axitinib (Inlyta). Axitinib, which is currently approved for use as a second-line therapy for RCC, is also included in the NCCN guidelines as a potential rst-line therapy for use in advanced RCC.

In December 2017, the FDA granted this combination a Breakthrough Therapy designation for the treatment of previously untreated patients with advanced RCC. The designation is intended to expedite the development of the regimen in the specified setting when preliminary clinical evidence indicates that it may produce a substantial improvement over current therapies based on 1 or more clinically significant endpoints.

The designation was based on findings from the phase Ib JAVELIN Renal 100 trial.5 In the study, frontline avelumab/axitinib induced a response rate of 58.2% in patients with advanced RCC. The CR rate was 5.5%, the partial response rate was 52.7%, and the disease control rate was 78.2%. The investi- gators, led by Toni K. Choueiri, MD, of Dana-Farber Cancer Institute, hypothesized that combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action.

Fifty-five treatment-na&iuml;ve patients were enrolled in JAVELIN. Participants received avelumab 10 mg/ kg IV every 2 weeks and 5-mg oral axitinib twice daily until disease progression, unacceptable toxicity, or withdrawal. The majority of enrolled patients (96.4%) had favorable or intermediate-risk disease per MSKCC criteria. Primary endpoints included safety and objective response as measured by RECIST v1.1.

Patients were also evaluated by PD-L1 expression. At a cutoff of &ge;1% PD-L1 expression, the ORR was 65.9% (27/41) in PD-L1—positive patients and 36.4% (4/11) in PD-L1&ndash;negative patients (odds ratio [OR], 3.38; 95% CI, 0.70-18.12). At the 5% cutoff, the ORR was 67.9% (19/28) in PD-L1&ndash;positive patients and 50.0% (12/25) in PD-L1&ndash;negative patients (OR, 2.11; 95% CI, 0.60-7.57). PFS and OS data are not yet mature.

The median duration of treatment was 66.6 weeks with axitinib and 66.0 weeks with avelumab. At cutoff, treatment was ongoing in 52.7% of patients. Fifty-three patients (96.4%) had an avelumab- or axitinib-related AE with the therapy combination. AEs caused 7 patients to discontinue avelumab and 4 to discontinue axitinib.

The most common all-grade AEs were diarrhea (58.2%), hypertension (47.3%), dysphonia (47.3%), and fatigue (45.5%). Most infusion-related reactions were grade 1 or 2 and occurred mainly during the first 2 infusions of avelumab.

With more serious AEs, 26 patients experienced grade 3 AEs, while 5 had grade 4 AEs. One patient died due to myocarditis, the only immune-related AE that led to death. Just 3 of 17 immune-related AEs were grade 3.

Choueiri et al concluded that the safety pro le of the combination of avelumab and axitinib appears manageable and consistent with each agent used as mono- therapy. They characterized early antitumor activity as encouraging and note that follow-up is ongoing.

PEMBROLIZUMAB + LENVATINIB

In January 2018, the FDA granted a Breakthrough Therapy designation to the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima). Pembrolizumab is a PD-1 inhibitor and lenvatinib is a VEGF/FGF inhibitor.

The FDA based its designation on data from the RCC cohort of the multicenter open-label phase Ib/II Study 111, which is assessing the safety and ef cacy of the combination treatment in patients with various solid tumors.⁶Study 111&rsquo;s primary objective is to determine the maximum-tolerated dose of the combination. The agency responded favorably to news that patients treated with the combination had an ORR of 63.3% (95% CI, 43%-80%).

The phase Ib portion of Study 111 enrolled 8 patients with RCC who had progressed after treatment with approved therapies. Investigators settled on a daily dose of 20 mg of lenvatinib based on toxicity reports. They continued this dosage into phase II, which included 22 patients with RCC. Of the 30 total patients between phase Ib and phase II, 12 were treatment-na&iuml;ve and 18 had received prior treatment; 5 of whom had &ge;3 prior regimens. Previous treatment with a VEGF-targeted therapy was noted in 16 patients.

During phase II, patients with lenvatinib toxicities received reduced doses of the drug (from 14 mg down to 10, 8, and then 4, if needed); dose re-escalation was not permitted. Pembrolizumab toxicities were managed with dose interruptions from the usual schedule of 200 mg every 3 weeks.

All responses were partial responses. The ORR at 24 weeks was 83% (95% CI, 52%-98%) in the treatment-na&iuml;ve cohort and 50% in those patients who received previous treatment. The median duration of response was not yet reached for the total cohort and the treatment-na&iuml;ve cohort when ndings were reported at the ESMO Congress in September 2017. The median duration of response was 8.5 months in the pretreated cohort.

Further, the median PFS had not yet been reached at the time of data cutoff. Ten of 12 previously untreated patients remained on treatment.

Lead author Chung-Han Lee, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, reported at ESMO that objective responses could be seen in both the PD-L1—positive (n = 12) and PD-L1&ndash;negative populations. &ldquo;They appear to be similar, with 58% of the PD-L1&ndash;positive patients and 71% of PD-L1&ndash;negative patients achieving objective responses,&rdquo; he said.

According to Lee, an extended duration of response could be seen in both PD-L1—positive and PD-L1&ndash; negative patients. &ldquo;In the treatment-na&iuml;ve cohort, prolonged stable disease could also be seen in PD-L1&ndash;positive patients who remained on therapy at 12 months,&rdquo; he said. &ldquo;In the previously treated patients, 6 of 18 patients remain on treatment, with 1 patient having a duration of response greater than 8 months.&rdquo; Of 30 patients, 28 experienced tumor shrinkage, with no clear association between changes in tumor size and PD-L1 staining status.

Treatment-emergent AEs (TEAEs) led to reductions in the lenvatinib dose in 18 patients. The most common any-grade TEAEs were diarrhea (83%), fatigue (70%), hypothyroidism (67%), stomatitis (60%), hypertension (57%), and nausea (57%). Two grade 5 TEAEs were both related to disease progression and not deemed to be related to treatment.

WHAT&rsquo;S AHEAD IN CLINICAL PRACTICE

As Fishman reflects on the many changes and advances in RCC treatment, he is reminded of the common pattern of most patients receiving a VEGF drug as initial therapy. &ldquo;Some high-risk patients were getting mTOR therapy upfront, and many others were getting mTOR therapy at some point after the VEGF treatment,&rdquo; he says. &ldquo;Then, in the last year or two as everolimus lost trials to sunitinib and nivolumab and cabozantinib and the everolimus/lenvatinib combina- tion, we saw the mTOR drugs pushed down the list and sometimes off it entirely.&rdquo;

In the near future, Fishman expects guidance for clinicians to remain murky. &ldquo;We may all be in a muddle of not knowing which of several 2-part combinations should be prioritized,&rdquo; he said. &ldquo;Once all of these trials have matured, we&rsquo;re going to very quickly get to a situation like we had had with the VEGF drugs where there are several good choices but no proper head-to-head comparisons.&rdquo;

The recent spate of trials has also convinced Fishman, who is a member of the chemical biology and molecular medicine program at Moffitt, that molecular testing will continue to yield clinically relevant information. &ldquo;A focus on PD-L1 is going to creep into the algorithm and help guide our clinical choices,&rdquo; he says. &ldquo;That&rsquo;s not going to be universally accepted, but there&rsquo;s relevant information there. Maybe we&rsquo;ll be able to step away from the more clinical risk factor stratification that has dominated for the last decade, which would be a proper scientific evolution.&rdquo;

References:

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Kidney Cancer. Version 3.2018. NCCN website. nccn.org/professionals/physician_gls/ pdf/kidney.pdf. Published February 6, 2018. Accessed February 27, 2018.
2. Escudier B, Tannir N, McDermott DF, et al. CheckMate 214: e cacy and safety of nivolumab + ipilimumab v sunitinib for treatment-naive advanced or metastat- ic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Ab- stract LBA5. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/ CheckMate-214-E cacy-and-safety-of-nivolumab-ipilimumab-N-I-v-sunitinib-S- for-treatment-naive-advanced-or-metastatic-renal-cell-carcinoma-mRCC-includ- ing-IMDC-risk-and-PD-L1-expression-subgroups.
3. Powles T, McDermotee SF, Rini B, et al. IMmotion150: novel radiological end- points and updated data from a randomized phase II trial investigating atezoli- zumab (atezo) with or without bevacizumab (bev) vs sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC). Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA39. oncologypro.esmo. org/Meeting-Resources/ESMO-2017-Congress/IMmotion150-Novel-Radiolog- ical-Endpoints-and-Updated-Data-From-a-Randomized-Phase-II-Trial-Investigat- ing-Atezolizumab-atezo-With-or-Without-Bevacizumab-bev-vs-Sunitinib-sun-in-Un- treated-Metastatic-Renal-Cell-Carcinoma-mRCC.
4. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC).J Clin Oncol.2018;36(suppl 6S; abstr 578). meetinglib- rary.asco.org/record/156867/abstract.
5. Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as rst-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose- nding and dose-expansion, phase 1b trial [published online March 9, 2018].Lancet Oncol.doi: 10.1016/S1470-2045(18)30107-4.
6. Lee C, Makker V, Rasco D, et al. A phase 1b/2 trial of lenvatinib plus pembroli- zumab in patients with renal cell carcinoma. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 847O. oncologypro.esmo.org/ Meeting-Resources/ESMO-2017-Congress/A-Phase-1b-2-Trial-of-Lenvatinib- Plus-Pembrolizumab-in-Patients-With-Renal-Cell-Carcinoma.