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Designing novel immunocombinations in metastatic renal cell carcinoma Matteo Santoni1 , Francesco Massari*, ‡ ,2 , Gaetano Aurilio3 , Veronica Mollica2 , Alessia Cimadamore4 , Antonio Lopez-Beltran5 , Liang Cheng6 , Nicola Battelli1 , Franco Nole´ 2 & Rodolfo Montironi4 1

Oncology Unit, Macerata Hospital, Macerata, Italy Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni – 15, Bologna – Italia 3 Medical Oncology Division of Urogenital & Head & Neck Tumours, IEO, European Institute of Oncology IRCCS, Milan, Italy 4 Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy 5 Department of Surgery, Cordoba University Medical School, Cordoba, Spain 6 Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA *Author for correspondence: [email protected] ‡ Authors contributed equally 2

Immune checkpoint inhibitors have radically changed the treatment approach to metastatic renal cell carcinoma (mRCC). In the present article, we reported and discussed the available data with immunocombinations in mRCC, offering new perspectives in the treatment landscape of these patients. We discussed the main results of pivotal clinical trials of immune checkpoint inhibitors in the treatment of mRCC. Moreover, we discussed novel immuno-based treatments currently under investigation in ongoing clinical trials. Renal cell carcinoma is a particularly immunogenic tumor and immunotherapy is a pivotal treatment approach. A wide series of clinical trials is exploring novel promising immunocombinations in patients with renal cell carcinoma. First draft submitted: 15 May 2020; Accepted for publication: 10 September 2020; Published online: 1 October 2020 Keywords: atezolizumab • avelumab • immunotherapy • ipilimumab • nivolumab • PD-1 • PD-L1 • pembrolizumab

• RCC • renal cell carcinoma

Renal cell carcinoma (RCC) is one of the most immunogenic cancers [1,2]. Prior to 2005, in patients with metastatic RCC (mRCC), two cytokine therapies such as high-dose IL-2 and IFN-α were the therapeutic cornerstones. However, both these agents were associated with relevant toxicity and poor outcomes [3]. In the following years, the development of targeted therapies incorporating VEGFR (i.e., sunitinib, pazopanib, axitinib, sorafenib) inhibitors [4] and (mTOR, everolimus and temsirolimus) [5] and more recently the emerging of novel immunotherapies in mRCC patients have strongly contributed to enlarge the therapeutic landscape of this disease [6]. Immune checkpoint inhibitors (ICIs) are used to restore the immune response against the tumor with the inhibition of checkpoint receptors or their ligands, like programmed death receptor-1/programmed death receptorligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). ICIs have been tested in various lines of therapy and combinations in the treatment algorithm of mRCC [7,8]. Antibodies that target CTLA-4, such as ipilimumab and those that target PD-1, such as nivolumab, have been approved for their use in mRCC, in combination as first-line therapy for patients with intermediate or poorrisk disease [9], while as monotherapy nivolumab in mRCC patients progressing to prior therapy [10]. These two ICIs have significantly improved the survival outcomes of mRCC patients, overall revolutionizing the sequencing treatment that originally was exclusively based on VEGFR tyrosine kinase inhibitors (TKIs). This scenario has become even more intriguing when considering novel front-line options exhibiting successful survival data with ICIs and TKIs combinations, in other words, pembrolizumab (anti-PD-1) plus axitinib [11], avelumab (anti-PDL1) plus axitinib [12] and with ICIs and anti-VEGF antibodies, in other words, atezolizumab (anti-PD-L1) plus bevacizumab [13].

C 2020 Future Medicine Ltd 10.2217/imt-2020-0144 

Immunotherapy (Epub ahead of print)

ISSN 1750-743X

Review

Santoni, Massari, Aurilio et al.

An important challenge to address with the advent of immunotherapy and the expansion of the treatment scenario is the need to find and validate predictive and prognostic biomarkers to better guide treatment strategies, as discussed later. Notwithstanding the advances obtained with immunotherapy approaches, there is still a subset of nonresponder patients and progression of disease is still an inevitable consequence of the natural history of these patients. With the expanding knowledge on biological characteristics of RCC and resistance mechanisms to immunotherapy and TKIs, increasing efforts are being made to investigate combination therapies or explore novel immunotherapy approaches, involving other immunological pathways [14]. Regarding first line treatments, patients experiencing progressive disease (PD) as best response were 20% in Checkmate-214 [9] and 11% in Keynote-426 and JavelinRenal-101 [12,13]. Immune response depends on a multitude of factors, regarding the patient, the tumor and the microenvironment. Many costimulatory or corepressory factors can promote or inhibit immune response against the tumor and PD-1/PD-L1 is just one of them. Consequently, combination strategies of anti-PD-1/PD-L1 with other immunotherapy approaches targeting these other pathways are of interest to overcome resistance. Among these, checkpoint inhibitors that are acts as co-inhibitory molecules are lymphocyte activation gene 3 (LAG-3, CD223), T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) and indoleamine 2,3-dioxygenase (IDO) 1 while costimulatory receptors are glucocorticoid-induced TNFR-related protein (GITR) and TNFR superfamily, member 4 (OX40) [14]. Novel immunotherapy combination approaches are being evaluated to overcome resistance deriving from the dysregulation of these pathways. Based on this scenario, in the present article the authors report and discuss the available data with immunocombinations in mRCC, offering new perspectives in the treatment landscape of these patients. Throughout this review, the authors will discuss the current status of immunocombination in the treatment of mRCC and novel immunotherapy approaches, including combination with anti-PD-1/PD-L1, anti-CTLA-4, adaptative trials, combination with radiotherapy and novel immunotargets. Immunocombinations in mRCC: current results Regarding first-line treatments in mRCC, to date the results of four randomized Phase III trials have been published and have changed the standard of care of untreated patients: one (CheckMate-214), evaluated the combination of a PD-1 inhibitor, nivolumab, with the anti-CTLA-4 ipilimumab while the others (Javelin-Renal 101, Keynote426 and IMmotion-151) tested the combination of an anti PD-1 or PD-L1 with a target agent, like axitinib or bevacizumab [9,11–13,15]. Of note, all these trials enrolled patients with mRCC with a clear cell component. PD-1 and CTLA-4 are two of the main inhibitory pathways of the immune response so the combination of ICIs that target both receptors has the purpose of restoring T-cell activity. The biological rationale of combining a targeting agent with immunotherapy lies on the ability of anti-angiogenic therapies to normalize tumor vascularization and activate endothelial cells: this can induce a higher infiltration of T cells into the tumor bed, thus enhancing the effect of the PD-1/PD-L1 blockade [13]. CheckMate-214 [9] compared the combination of nivolumab plus ipilimumab with sunitinib in 1096 patients: the experimental arm resulted to be superior in all three primary end points, which were overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) among patients with intermediate and poor risk according to International Metastatic RCC Database Consortium (IMDC) criteria (Table 1). The results of the extended follow-up (30 months) [15] have been recently published: in the intermediate and poor population, median OS was not reached in nivolumab/ipilimumab arm versus 26.6 months in sunitinib arm (hazard ratio [HR]: 0.66; 95% CI: 0.54–0.80), median PFS was 8.2 months with nivolumab/ipilimumab versus 8.3 months with sunitinib (HR: 0.77, 95% CI: 0.65–0.90), ORR favored nivolumab/ipilimumab (42 vs 29%). In the favorable group, OS was not reached in both treatment arms (HR: 1.22; 95% CI: 0.73–2.04), ORR favored sunitinib (39% in nivolumab/ipilimumab arm vs 50% in sunitinib arm). The exciting data deriving from this combination is the extremely high percentage of complete responses (CR) achieved, 11% with the combination versus 1% of sunitinib in intermediate and poor risk patients. Javelin-Renal 101 evaluated the combination of the anti-PD-L1 avelumab with the TKI axitinib versus sunitinib in 886 patients (Table 1) [12]. The co-primary end points were OS and PFS in patients expressing PD-L1 (assessed by Ventana SP263 assay). The trials showed a higher PFS for the combination arm both in the PD-L1 positive (HR: 0.61; 95% CI: 0.47–0.79) and overall population (HR: 0.69; 95% CI: 0.56–0.84). OS data are still immature. ORR was significantly higher in the experimental arm in PD-L1 positive (55.2 vs 25.5%) and overall population (51.4 vs 25.7%).

10.2217/imt-2020-0144

Immunotherapy (Epub ahead of print)

future science group

Immunotherapy in RCC

Review

Table 1. Studies on immunocombinations approved for advanced renal cell carcinoma. Study

Setting

Drugs

Targets

Median OS

Median PFS

ORR

CheckMate-214

First-line (intermediate, poor risk)

Nivolumab and ipilimumab

PD-1 and CTLA-4

Intermediate and poor risk – Exp: NR – Control: 26.6 months HR: 0.66 95% CI: 0.54–0.80

Intermediate and poor risk – Exp: 8.2 months – Control: 8.3 months HR: 0.77 95% CI: 0.65–0.90

Intermediate and poor risk – Exp: 42% – Control: 29%

Keynote-426

First-line

Pembrolizumab plus axitinib vs sunitinib

PD-1

– Exp: NR – Control: NR HR: 0.53 95% CI: 0.38–0.74

– Exp: 15.1 months – Control: 11.1 months HR: 0.69 95% CI: 0.57–0.84

– Exp: 59.3% – Control: 35.7%

Javelin renal 101

First-line

Avelumab plus axitinib vs sunitinib

PD-L1

Not mature follow-up

Overall – Exp: 13.8 months – Control: 8.4 months HR: 0.69 95% CI: 0.56–0.84

Overall – Exp: 51.4% – Control: 25.7%

PD-L1+ – Exp: 13.8 months – Control: 7.2 months HR: 0.61 95% CI: 0.47–0.79 Immotion-151

First-line

Atezolizumab plus bevacizumab vs sunitinib

PD-L1

PD-L1+ – Exp: 55.2% – Control: 25.5%

Overall – Exp: 33.6 months – Control: 34.9 months HR: 0.93 95% CI: 0.76–1.14

Overall – Exp: 11.2 months – Control: 8.4 moths HR: 0.83 95% CI: 0.70–0.97

Overall – Exp: 37% – Control: 33%

PD-L1+ – Exp: 34.0 months – Control: 32.7 months HR: 0.84 95% CI: 0.62–1.15

PD-L1+ – Exp: 11.2 months – Control: 7.7 months HR: 0.74 95% CI: 0.57–0.96

PD-L1+ – Exp: 43% – Control: 35%

CTLA-4: Cytotoxic T-lymphocyte antigen-4; Exp: Experimental; HR: Hazard ratio; ORR: Overall response rate; OS: Overall survival; PD-1: Programmed death-1; PD-L1: Programmed death-ligand-1; PFS: Progression-free survival.

The combination of the anti-PD1 pembrolizumab with axitinib versus sunitinib was evaluated in the KEYNOTE426 trial in 861 patients (Table 1) [11]. The co-primary end points were PFS and OS in intention-to-treat population. The combination arm resulted to be superior in terms of OS (HR: 0.53; 95% CI: 0.38–0.74) and PFS (HR: 0.69; 95% CI: 0.57–0.84). Also, ORR favored the combination arm (59.3 vs 35.7%). IMmotion-151 compared the combination of the anti-PD-L1 atezolizumab with bevacizumab, a monoclonal antibody targeting VEGF, versus sunitinib (Table 1) [13]. The co-primary end points were PFS in PD-L1 (assessed by Ventana SP142 assay) expressing patients and OS in intention-to-treat population. This trial showed that the combination improved PFS in PD-L1 positive patients (HR: 0.74; 95% CI: 0.57–0.96) and intention-to-treat population (HR: 0.83, 95% CI: 0.70–0.97), but OS was similar between the two arms in PD-L1 expressing and intention-to-treat population (HR: 0.93; 95% CI: 0.76–1.14 and HR: 0.84; 95% CI: 0.62–1.15, respectively). The knowledge on the efficacy of immunotherapy in nonclear cell RCC (nccRCC) is less extended because patients with this histology are often excluded from clinical trials. The combination of atezolizumab and bevacizumab was tested in a Phase II, single-arm trial in patients with nccRCC and ccRCC with sarcomatoid component in first or later lines [16]. The combination was proved to have antitumor activity with an ORR of 31%. The Phase II, single arm KEYNOTE-427 cohort B showed the efficacy of pembrolizumab in first line of treatment in patients with nccRCC with an ORR of 24.8%, with a better response in papillary and unclassified histology [17]. Ongoing clinical trials will help assess the efficacy of immunotherapy in this subset of patients. Ongoing clinical trials exploring novel immunocombinations in mRCC Combinations including anti-PD-1 agents

The list of anti-PD-1 agents currently under investigation in RCC includes nivolumab, pembrolizumab, camrelizumab and PDR001. Nivolumab, in particular, is under examination in combination with anti-MET inhibitors cabozantinib, sitravatinib and APL-101. Thus, nivolumab plus cabozantinib is under investigation in the CytoKIK Phase II study, administered as neoadjuvant therapy before nephrectomy (NCT04322955, Table 2), while

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Table 2. Ongoing trials investigating combinations including antiprogrammed death-1 or antiprogrammed death-ligand-1 agents in renal cell carcinoma. Agents

Target

Trial ID number

Phase

Description

Nivolumab

PD-1

NCT02293980

I

In combination with small-molecule inhibitor anti-HIF2␣ PT2385 in mRCC

NCT02946671

I

In combination with cytokine modulator anti-CCR4 mogamulizumab in mRCC

NCT04074967

I/II

In combination with dual p38 MAPK/Tie2 inhibitor pexmetinib (ARRY-614) in mRCC

NCT03655613

I/II

In combination with anti-c-MET agent APL-101 in mRCC

NCT03015740

I/II

In combination with multikinase inhibitor sitravatinib in mRCC

NCT04322955

II

In combination with cabozantinib as neoadjuvant therapy before nephrectomy

Pembrolizumab

PD-1

NCT03149822

I/II

In combination with cabozantinib in mRCC

NCT03736330

II

Autologous dendritic and cytokine-induced killer cells D-CIK incubated with low pembrolizumab and transferred to participants with mRCC

NCT02811861

III

In combination with lenvatinib compared with lenvatinib plus everolimus or sunitinib in mRCC as first-line therapy

Camrelizumab

PD-1

NCT03987698

II

In the second-line therapy after progression with interferon or TKIs, in combination autologous CIK cells 1 × 10∧10 at day 14 every 3 weeks for 4 cycles followed by camrelizumab as maintanance therapy

PDR001

PD-1

NCT03207867

II

In combination with A2AR antagonist NIR178 in non-Hodgkin lymphoma or solid tumors including RCC

Atezolizumab

PD-L1

Avelumab

Durvalumab

PD-L1

PD-L1

NCT03063762

I

In combination with bevacizumab and RO6874281 in patients with mRCC

NCT03024437

I/II

In combination with bevacizumab and Entinostat in patients with mRCC

NCT03170960

I/II

In combination with cabozantinib in mRCC

NCT03961698

II

In combination with bevacizumab and IPI-549 in mRCC

NCT03200587

I

In combination with cabozantinib in mRCC

NCT04068831

II

In combination with PARP inhibitor talazoparib in mRCC

NCT03308396

I/II

In combination with guatecitabine in mRCC

NCT03598816

II

In combination with anti-CTLA-4 tremelimumab and neoantigen DNA vaccine in mRCC

NCT03741426

II

In combination with olaparib compared with durvalumab alone, olaparib alone or cediranib used alone or together with durvalumab or olaparib in mRCC

NCT04262375

II

In combination with oleclumab in mRCC

NCT03288532

III

In combination with tremelimumab as adjuvan therapy for localized RCC

A2AR: Adenosine A2a receptor; CIK: Cytokine-induced killer; D-CIK: Dendritic and cytokine-induced killer cells; HIF2␣: Hypoxia-induced factor 2␣; mRCC: Metastatic renal cell carcinoma; PARP: Poly ADP-ribose polymerase; PD-1: Programmed death-1; PD-L1: Programmed death-ligand-1; TKI: Tyrosine kinase inhibitor.

two Phase I/II trials are exploring the combination of nivolumab and APL-101 (NCT03655613) or sitravatinib (NCT03015740) in mRCC patients (Table 2). Sitravatinib (MGCD516) is a small multi-TKI that has been found to potentiate immune checkpoint blockade and is involved in many signaling pathways, such as TYRO3, AXL, MerTK, VEGFR, PDGFR, KIT, RET and MET [18]. On the other hand, nivolumab is under study in combination with dual p38 MAPK/Tie2 inhibitor pexmetinib (ARRY-614, NCT04074967), antihypoxia-induced factor-2α PT2385 (NCT02293980) or cytokine modulator anti-CCR4 mogamulizumab (NCT02946671) in patients with advanced RCC (Table 2). Regarding hypoxia-induced factor-2α, this is an important pathway in RCC because it degradation is regulated by Von Hippel-Lindau (VHL), the most frequently altered gene in clear cell RCC. The accumulation of HIF1-2α consequent to VHL loss in RCC leads to up-regulation of hypoxia-response elements (VEGF, PDGF, EGF and GLUT1) [19]. Pexmetinib is an orally bioavailable small-molecule inhibitor of p38 and Tie2, that are often upregulated in tumor cells. P38 is a MAP kinase crucial for the production of cytokines like TNF and IL-1 and IL-6. Tie2 is an endothelial cell specific receptor that is activated by angiopoietins, essential for angiogenesis. Through p38 and Tie2 inhibition, the production of pro-inflammatory cytokines is decreased, leading to the reduction of tumor angiogenesis, tumor cell growth and survival. As for pembrolizumab, three different studies are evaluating its efficacy and safety in combination with lenvatinib (NCT02811861), cabozantinib (NCT03149822) or autologous dendritic and cytokine-induced killer (CIK) cells (NCT03736330).

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Immunotherapy (Epub ahead of print)

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Immunotherapy in RCC

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Table 3. Ongoing trials investigating combinations including anti-PD-1/PD-L1 and anti-CTLA-4 agents in renal cell carcinoma. Agents

Target

Trial ID number

Phase

Description

Nivolumab and iIpilimumab

PD-1 and CTLA-4

NCT02496208

I

In combination with cabozantinib in treating patients with metastatic genitourinary tumors

NCT03829111

I

In combination with Clostridium butyricum probiotic CBM 588 in mRCC

NCT02983045

I/II

In combination with NKTR-214 in patients with advanced solid tumors including RCC

NCT04203901

II

In combination with CMN-001 as first-line and, after progression, followed by CMN-001 with everolimus and lenvatinib as second-line therapy

Durvalumab and tremelimumab

PD-L1 and CTLA-4

NCT03866382

II

In combination with cabozantinib for rare genitourinary tumors

NCT03141177

III

In combination with cabozantinib compared with cabozantinib alone or sunitinib in mRCC

NCT02762006

I

As neoadjuvant therapy in patients with localized RCC

mRCC: Metastatic renal cell carcinoma; PD-1: Programmed death receptor-1; PD-L1: Programmed death receptor-ligand 1; RCC: Renal cell carcinoma.

In the second-line therapy after progression with interferon or TKIs, another Phase II study is exploring the combination of anti-PD-1 agent camrelizumab (SHR-1210) 200 mg administered at day 1 and autologous CIK cells 1 × 10∧10 at day 14 every 3 weeks for 4 cycles followed by camrelizumab as maintanance therapy (NCT03987698). Emerging combinations including anti-PD-L1 agents

A Phase I/II study is evaluating atezolizumab in combination with cabozantinib (NCT03170960) in mRCC. In addition, three different clinical trials have been designed to explore the addiction to atezolizumab plus bevacizumab of RO6874281, an engineered variant of IL-2 (IL-2v) targeted to tumor-associated fibroblasts (NCT03063762), entinostat, a benzamide histone deacetylase (HDAC) inhibitor (NCT03024437) or IPI-549 is an oral, selective inhibitor of PI3K gamma (NCT03961698) in mRCC (Table 2). As known epigenetic mechanisms, such as histone acetylation or deacetylation, are crucial for gene expression. Acetylation leads to increased DNA accessibility while deacetylation results in lower DNA accessibility and gene silencing [20]. The HDAC inhibitor entinostat selectively inhibits class I and IV HDACs, leading to histone acetylation, gene transcriptional activation, and subsequent cell proliferation inhibition, terminal differentiation and apoptosis. IPI-549 is a PI3K-gamma inhibitor, that prevents the activation of the PI3K-gamma-mediated signaling pathways and reduction of proliferation of PI3K-gamma expressing cells [21]. The gamma isoform is often expressed in immune cells or tumor cells and is limited in normal epithelial cells and connective tissue, thus its inhibition minimally affects non-neoplastic cells. The inhibition of PI3K-gamma in tumor-associated myeloid cells can modulate antitumor immune responses and inhibit tumor-mediated immunosuppression, leading to enhanced immune attack on tumor cells. As for Avelumab, two Phase I and II trials are, respectively, investigating its efficacy and safety in combination with cabozantinib (NCT03200587) or poly ADP-ribose polymerase inhibitor talazoparib (NCT04068831) in patients with advanced RCC (Table 2). Finally, five studies are recruiting patients to assess durvalumab in combination with tremelimumab as adjuvant therapy (NCT03288532) and administered with guatecitabine (a dinucleotide antimetabolite of a decitabine, NCT03308396) or anti-CTLA-4 tremelimumab and neoantigen DNA vaccine (NCT03598816) or olaparib (WIRE study, NCT03741426) or oleclumab (a human anti-CD73 monoclonal antibody, NCT04262375) in mRCC (Table 2). Novel combinations including anti-PD-1/PD-L1 & anti CTLA-4 agents

The combination of cabozantinib, nivolumab and ipilimumab is under study in a Phase I study in patients with metastatic genitourinary tumors (NCT024962089, in a Phase II trial enrolling patients with rare genitourinary tumors (NCT03866382) and in a Phase III study comparing this combination to cabozantinib alone or sunitinib (NCT03141177, Table 3).

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Santoni, Massari, Aurilio et al.

On the other hand, a Phase I/II trial (NCT02983045) is testing nivolumab plus ipilimumab and bempegaldesleukin (NKTR-214), which binds to CD122 (a subunit of the IL-2 receptor, a protein expressed in natural killer and CD8 T cells), in patients with solid tumors including RCC (Table 3). Moreover, a Phase II trial is in course in patients with RCC and prevalent clear cell histology relapsed within 1 year from initial diagnosis to investigate CMN-001, an autologous tumor antigen-loaded dendritic cell immunotherapy, in combination with nivolumab plus ipilimumab as first line and, after progression, administered during oral treatment with Everolimus and Lenvatinib as second-line therapy (NCT04203901). Finally, a Phase I study (NCT03829111) is evaluating the efficacy and safety of Clostridium butyricum CBM 588 probiotic strain in combination with nivolumab and ipilimumab for patients with stage IV RCC (Table 3). Regarding anti-PD-L1 agents, durvalumab combined with anti-CTLA-4 tremelimumab is ongoing as neoadjuvant treatment in a Phase I study in previously untreated localized RCC patients (NCT02762006, Table 3). Adaptative designs

Adaptative designs have been investigated as ways to improve current immunotherapy strategies considering that not all patients may require upfront intensified schedules and that the addition of ipililmumab to nivolumab may be needed only in patients not achieving good responses with nivolumab monotherapy. Recently, the preliminary results of four adaptative trials have been presented. OMNIVORE (NCT03203473) is a Phase II response-adaptive trial investigating the sequential addition of two doses of ipilimumab to induce response in nivolumab nonresponders and duration of nivolumab in responding patients [22]. 83 patients with mRCC with no prior checkpoint inhibitor exposure were enrolled. The primary end points were the proportion with partial responses (PR)/CR at 1-year after nivolumab discontinuation (Arm A) and proportion of nivolumab nonresponders who convert to PR/CR after adding ipilimumab (Arm B). In Arm A, patients with PR or CR within 6 months discontinued nivolumab and were observed; in case of PD they reinitiated nivolumab and ipilimumab was added to nivolumab if PD persisted or recurred. Patients with stable disease (SD) or PD after no more than 6 months of nivolumab alone received two doses of ipilimumab (Arm B). This approach resulted in unsatisfactory results in terms of CR (absent) or PR/CR conversion rate (4%), so it cannot be recommended. At 6 months, induction nivolumab resulted in confirmed PR in 11% of patients. A subset of patients undergoing nivolumab monotherapy maintained durable responses off treatment at 1 years (42%); nonetheless, early nivolumab discontinuation in the absence of toxicity cannot be recommended. TITAN-RCC (EudraCT: 2016-002307-26) is another study evaluating an adaptative approach in 258 patients with intermediate and poor risk clear cell mRCC [23]. Patients started with nivolumab induction; patients with early significant PD (week 8) or either SD or PD at week 16 received 2–4 nivolumab plus ipilimumab boost cycles. Responders (PR/CR) to nivolumab monotherapy continued with maintenance with nivolumab plus ipilimumab boosts only for progression. This approach resulted to significantly improve ORR compared with nivolumab monotherapy in first line treatment. Confirmed ORR, the primary end point, with first line nivolumab monotherapy was 28.7%. 102 patients received nivolumab plus ipilimumab boosts for either SD or PD until week16. Of these, 12 and 53% had a PR/CR and SD, respectively. HCRN GU16-260 (NCT03117309) is a Phase II trial that enrolled 123 treatment naive clear cell RCC patients, that received nivolumab 240 mg IV q2 weeks for 6 doses followed by 360 mg IV q3 weeks for 4 doses followed by 480 mg q4 weeks until PD, toxicity or completion of 96 weeks of treatment (Part A) [24]. Patients with PD prior to or SD at 48 weeks were potentially eligible to receive salvage nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) q3 weeks for 4 doses followed by q4 weeks nivolumab maintenance for up to 48 weeks (Part B). Salvage treatment with nivolumab plus ipilimumab combination resulted to feasible in patients with PD or SD and these patients responded to combination therapy in 11% of cases. In particular, ORR was 29.3%, with 4.3% CR, 24.8% PR, 40.2% SD, 30.7% PD. Best response to nivolumab plus ipilimumab was PR (11%), SD (30%), PD (59%). Nivolumab monotherapy resulted to be active as first line treatment but combination approach is likely preferred, especially for intermediate- and poor-risk patients. The last of these adaptative design study recently presented is FRACTION-RCC (NCT02996110) [25]. In this Phase II trial, 46 patients progressed on previous checkpoint inhibitor therapy received nivolumab plus ipilimumab (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3 weeks for 4 cycles, then after 6 weeks, nivolumab 480 mg q4 weeks), up to 2 years or until progression, or toxicity. ORR was 15.2%, no patients achieved CR, and 7 achieved PR. Duration of response ranged from 2–19 months. Durable and efficacy benefits were observed in a subgroup of patients post progression on ICIs.

10.2217/imt-2020-0144

Immunotherapy (Epub ahead of print)

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Immunotherapy in RCC

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Emerging combinations including immunotherapies & radiotherapy

Radiotherapy has started a second life since the advent of novel immunotherapies for mRCC [26,27]. The evidence of a synergistic effect of these two strategies has led to the design of clinical trials aimed to explore this combination in RCC. At this regard, four different Phase II trials are currently investigating the combination of radiotherapy plus nivolumab (NCT03115801), stereotactic body radiation therapy plus ipilimumab and nivolumab (NCT04090710 and NCT03065179) or atezolizumab plus hypofractionated stereotactic ablative radiotherapy (NCT02992912). At the recent ASCO Genitourinary Cancers Symposium 2020, two studies of combination between immunotherapy and radiotherapy have been presented. NIVES trial (NCT03469713) is a Phase II study of nivolumab combined with stereotactic body radiotherapy in 69 patients with mRCC progressed after 2 or less prior antiangiogenic therapies [28]. Hypofractionated radiation therapy was administered in one lesion at dose of 10 Gray (Gy) in three fractions after 7 days from the first infusion of nivolumab. This combination approach resulted to be generally well tolerated with an ORR of 19% (1 CR), a disease control rate of 63.5%, median PFS of 4 months and median OS of 22.1 months. Grade 3–4 adverse events related to nivolumab were experienced in 17 pts (24.6%) while no grade 3–4 toxicities related to stereotactic body radiotherapy were reported. RADVAX is a Phase II trial evaluating the combination of nivolumab plus ipilimumab with stereotactic body radiotherapy administered to 1 or 2 disease sites with a dose of 50 Gy in 5 fractions between the first and the second dose of immunotherapy [29]. 25 patients with mRCC, either previously untreated or treated with TKIs or cytokines, were enrolled. Combination treatment was found to have an acceptable safety and encouraging antitumor activity with ORR of 56% and 14 PR. Combinations based on novel immunotargets

As our knowledge grows on the activity of immune cells within RCC microenvironment, a series of novel combination strategies is emerging in the therapeutic landscape of this disease. The first example of this future approach is represented by the use of CIK cells. CIK cells are a heterogeneous population of effector CD3+ CD56+ NK T cells that can be easily expanded in vitro [30]. Due to their MHC-unrestricted and effective antitumor activity, CIK cells have emerged as a promising pharmacological tool. In order to expand the cytotoxicity of CIK cells, combinatory strategies are in course of investigation. We have already cited above the clinical trial evaluating CIK cells in combination with anti-PD-1 agent camrelizumab (NCT03987698). Interestingly, another Phase I/II study is ongoing to study CIK combined with dendritic cells-cytotoxic T lymphocytes in solid tumors including RCC (NCT03047525). The rational for the use of this combination comes from the evidence that CIK/dendritic cells-cytotoxic T lymphocytes can reduce Tregs, myeloid-derived suppressor cells and a series of serological tumor biomarkers including AFP, CA19-9, CA242 and CA724 [31]. Among emerging combinatory approaches, the possibility to combine polyethylene glycolylated IL-2 to cancer vaccine seems to be also very interesting. The DIRECT-01 study (NCT03548467) has been designed with at this scope. This Phase I/II trial involves the use of IL-2 pathway agonist NKTR-214 and VB10.NEO, an individualized highly potent DNA plasmid cancer vaccine. Indeed, this combination has been shown to obtain deep neoantigenspecific T-cell responses and durable complete tumor regressions in preclinical models, as presented by Stine Granum at American Association of Cancer Research (AACR) Annual meeting in Atlanta in 2019 [32]. In Figure 1 are depicted novel targets for immunocombinations in RCC. Discussion Immunotherapeutic strategies in mRCC include the use of cytokines, tumor vaccines, T-cell modulation and combined regimens. Notwithstanding real prognostic improvements, the majority of patients with mRCC still progress and continues to be correlated with high rates of both morbidity and mortality. Accordingly, how to overcome or improve current pitfalls of the therapeutic armamentarium has become a priority worldwide, and hence several investigations are focusing on: improving the knowledge of immunomodulators included costimulatory (CD27, ICOS) and co-inhibitory molecules (PD-1, PD-L1, PD-L2, CTLA4, LAG3, TIM-3, TIGIT, IDO1); testing new drugs with immunotherapy for novel combinations; combining the classes of therapies mentioned above, thinking for instance to the immunomodulatory effects of targeted therapies in tumor microenvironment; selecting the optimal sequence of treatment after front-line immunotherapy; identifying patients who are candidates for immunotherapy beyond progression. With all these new treatment strategies available, there are some open questions to address. Which combination should be preferred? Are there any factors that could help the clinician to identify the right patient for a specific combination treatment? Is there still room for a monotherapy approach with a TKI in first line of treatment?

future science group

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Review

Santoni, Massari, Aurilio et al.

Oleclumab

NKTR-214 Nivolumab Pembrolizumab Camrelizumab PDFR001

Mogamulizumab

Ipilimumab Tremelimumab

Atezolizumab Avelumab Durvalumab

ib

in

at nv

Le

Sitravatinib APL-101

Bevacizumab Oleclumab IPI-549

Renal cell carcinoma microenvironment

Figure 1. Novel targets for immunocombinations in renal cell carcinoma. CCR4: C-C Chemokine receptor type 4; CTLA-4: Cytotoxic T-lymphocyte antigen-4; FGF: Fibroblast growth factor; FGFR: FGF receptor; GF: Growth factor; GFR: GF receptor; HDAC: Histone deacetylase; HIF-2A: Hypoxia-induced factor-2A; IL-2R; IL-2 receptor; PARP: Poly ADP ribose polymerase; PD-1: Programmed death-1; PD-L1: PD-ligand 1; PDGF: Platelet-derived growth factor; PDGFR: PDGF receptor; VEGF: Vascular endothelial growth factor; VEGFR: VEGF receptor.

It should be underlined that all the first line trials have significant differences in terms of primary end points, population enrolled, median follow-up, so the results are not comparable. For example, the study with the longest follow-up is CheckMate-214 (30 months), while the median follow-up of Keynote-426 is 12.8 months and the follow-up of Javelin-renal 101 is not mature enough to evaluate a OS benefit [11–13,15]. Some factors to consider in order to choose the right treatment could be IMDC criteria, toxicity profiles and comorbidities, patients’ preference and the wished goal of the treatment. The combination of nivolumab plus ipilimumab is approved only for intermediate- and poor-risk patients according to IMDC criteria, while pembrolizumab or avelumab plus axitinib efficacy is independent from the class of risk [9,11,12]. PD-L1 expression did not result to be a predictive biomarker of efficacy of immunotherapy. In fact, in both CheckMate-025 and CheckMate-214 it was not shown a correlation between PD-L1 expression and clinical outcomes [9,10,15]. Moreover, toxicity profiles and patients’ comorbidities should be considered. As known, ICIs have to be avoided in patients with autoimmune diseases, in which a TKI monotherapy should be considered. An important factor to evaluate is the expected result: in fact, combining two ICIs could be a winning strategy in patients with a low tumor burden with the purpose of achieving a complete remission [9,15], while the combination of an ICI with a target agent could be useful in patients with high tumor burden and symptomatic disease in need of a fast tumor shrinkage, as supported by the high ORR of these types of combination [11,12]. An interesting exploratory analysis of the Phase II trial IMmotion-150 showed that patients with an angiogenic profile, which mainly expressed genes related to angiogenesis promotion, had better responses to sunitinib, while patients expressing a T-effector gene signature resulted to be associated with increased efficacy of both arms

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Immunotherapy in RCC

Review

containing atezolizumab (alone or in combination with bevacizumab) [33]. These results have been subsequently validated in an analysis of the Phase III IMmotion 151 trial [34]. Further efforts should be made to find and validate specific biomarkers that could help us accurately select patients in this evolving treatment scenario. At this regard, the BIOREN trial (NCT03628859) is ongoing to search for specific biomarkers of response in RCC patients treated with immunotherapy. Another interesting study in this field of research is the BIONIKK study (NCT02960906), a multicenter, randomized, Phase II biomarker driven trial with nivolumab and ipilimumab or VEGFR TKI in previously untreated clear cell mRCC. The aim of this study is to identify molecular groups of clear cell RCC that are able to define patients who will respond to nivolumab alone, nivolumab combined with ipilimumab, or TKIs (sunitinib or pazopanib). The lack of validated biomarkers of response to immunotherapy is opening the way to novel research approaches. One of the most interesting is represented by the analysis of volatile organic compounds, which are gases exhaled with a person’s breath and released into the lung from blood and bacteria. The use of special devices called electronic noses (eNose) is the focus of an observational ongoing study (NCT04146064) enrolling 425 patients with solid tumors treated with immunotherapy. This study, which will complete the enrollment in the next months, is aimed to identify, through a noninvasive tool, novel biomarkers of response in this setting. There is a clinical unmet need to find predictive and prognostic biomarkers in patients treated with immunotherapy and many scientific efforts are being made to address this issue. Recently, Braun and colleagues [35] published an integrated genetic, transcriptomic and immunopathologic analysis of advanced clear cell RCC tumors from 592 patients from three prospective clinical trials of PD-1 blockade [10,36,37]. This study is of particular interest because it gives an insight on immunogenomic mechanisms correlated to response to anti-PD-1. As known, clear cell RCC has a modest tumor mutational burden, but nonetheless it is responsive to ICIs [38]. Moreover, in this type of tumor high CD8+ T-cell infiltration, which is typically associated with response to immunotherapy, is correlated with worse prognosis [35]. Notably, in the analysis by Braun et al. no difference was found in terms of response to PD-1 inhibition in inflamed tumors (high CD8+ T-cell infiltration), immune excluded (CD8+ T cells are recruited to the tumor, but are unable to infiltrate the tumor core) and immune desert tumors (noninfiltrated) [35]. Immune inflamed tumors resulted to be depleted for PBRM1 mutations, that are correlated with improved survival with anti-PD-1 therapy and are enriched for chromosomal losses of 9p21.3, that are associated with worse outcome with PD-1 inhibitors. Furthermore, tumor mutation burden, neoantigen load and HLA zygosity were not associated with response to anti-PD-1 therapy [35]. Another study by Li et al. investigated the metabolic alterations in response to immune checkpoint blockade in patients with melanoma or RCC (from Checkmate-025 and CA209-009 trials) treated with nivolumab [39]. Kynurenine is a product of tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3dioxygenase and has been shown to suppress antitumor immune responses [40]. T Serum kynurenine/tryptophan ratio resulted to be increased in patients receiving nivolumab. Moreover, kynurenine/tryptophan ratio temporal alterations were found to be correlated with OS in these patients. This study points out that PD-1 inhibitors could be combined with IDO/tryptophan 2,3-dioxygenase inhibitors to enhance immune checkpoint blockade and this selected group of patients with checkpoint-inhibition triggered kynurenine pathway activation could benefit from this combination. A recently published study by Singla and colleagues analyzed the pancreatic tropism of RCC and characterized the clinical behavior and biology of this peculiar site of metastasis and the therapeutic implications [41]. Pancreatic metastases have been associated with a good prognosis and in this analysis resulted to be more resistant to immunecheckpoint inhibitors and respond better to antiangiogenic treatments. This behavior reflects the biology of these sites of metastasis, characterized by high frequency of PBRM1 mutations, 3p loss and 5q amplification and a low frequency of aggressive alteration, such as BAP1 mutations, loss of 9p, 14q and 4q. Moreover, pancreatic metastases appeared to present a reduced T-cell gene signatures and increased angiogenesis, thus supporting their sensitivity to antiangiogenic therapies and refractoriness to immunotherapy.

Conclusion In conclusion, a wide series of clinical trials is exploring novel immunocombinations in patients with localized and advanced RCC. The growing knowledge of the mechanisms underlying RCC immunogenicity and the efforts in finding effective predictive biomarkers of response will expand the therapeutic landscape of this disease in future years, leading to a moderate optimism about the possibility of selecting the best combination for each patient.

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Review

Santoni, Massari, Aurilio et al.

Future perspective Immuno-based combinations are the new standard of care for mRCC. As many immunotherapy approaches have already been validated and several other immune pathways are under investigation, many questions arise regarding the choice of the right treatment approach [42,43]. One of the main clinical issue to address in the immediate future is the pressing need for predictive and prognostic biomarkers adequate for patients undergoing an immunotherapy approach. The prognostic value of IMDC criteria, which are the most frequently used prognostic tool, may be increased with other variables to better evaluate the population of patients treated with immunotherapy. PD-L1 has not been validated as a biomarker of immunotherapy response in RCC patients. Primary site of metastasis has been explored as a prognostic biomarker [44]. Moreover, particular sites of metastasis seem to be more resistant to immunotherapy considering their peculiar biology, like pancreatic metastases [45]. Another issue to address in the future to better tailor the treatment strategy on the individual patient is to evaluate the efficacy of immunotherapy on nccRCC histologies, that present a different spectrum of molecular alterations. Moreover, it is still unknown which could be the best therapeutic sequence, considering the multiple treatment options at our disposal. Retrospective analyses or trial comparing treatment sequences could help to address this issue. In the future years, the results of the ongoing trials previously discussed will potentially generate new active treatments in RCC that can likely lead to a new horizon of therapeutic options, in which the clinician will face the hard task to individuate the best therapy for the individual patient. Executive summary • Immunotherapy changed the treatment scenario of metastatic renal cell carcinoma: combination of programmed death receptor-1/programmed death receptor-ligand 1 inhibitors with tyrosine kinase inhibitors or anti-CTLA-4 are the new standard of care of first line treatment. • Ongoing clinical trials are exploring novel immuno-combinations of antiprogrammed death receptor-1/programmed death receptor-ligand 1 or anti-CTLA-4 with other agents, like tyrosine kinase inhibitors, antihypoxia-induced factor-2α, histone deacetylase inhibitors. • Emerging combinations include also immunotherapies associated with radiotherapy. • Novel immunotarget therapies are being evaluated. Among these, cytokine-induced killer cells and cancer vaccines are of particular interest.

Author contributions ´ R Montironi, contributed to M Santoni, F Massari, G Aurilio, A Cimadamore, V Mollica, A Lopez-Beltran, L Cheng, N Battelli, F Nole, the conception and design of the study. M Santoni, F Massari, G Aurilio contributed to drafting the manuscript. A Cimadamore, V ´ R Montironi contributed to critical revision of the manuscript. All the authors Mollica, A Lopez-Beltran, L Cheng, N Battelli, F Nole, have approved the final version of the manuscript. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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