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Revisiting IL-2 Therapy in Renal Cell Carcinoma:
A Case Report of a Patient Treated With Pegylated IL-2, Bempegaldesleukin (NKTR-214)

Department of Genitourinary Medical Oncology
Division of Cancer Medicine
MD Anderson Cancer Center,
Houston, Texas


Keywords:  IL-2 therapy, nivolumab, bempegaldesleukin, immune checkpoint inhibitors, renal cell carcinoma, combination therapy.

 

Corresponding Author: Nizar M. Tannir, MD, FACP, Ransom Horne, Jr., Professor of Cancer Research, Professor and Chair ad interim. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, 1515 Holcomb Blvd., Unit 1374, Houston, TX 77030-4009  Email: ntannir@mdanderson.org

 

This cohort in PIVOT-02 is ongoing and full data analyses for the cohort are not yet available. Therefore, this patient case should be interpreted with caution.

 

Abstract

IL-2 is a well-known stimulatory cytokine involved in differentiation and activation of T-cells and natural killer (NK) cells. FDA approved high-dose IL-2, aldesleukin for the treatment of metastatic renal cell carcinoma (mRCC) in 1992 based on the phase 2 trial that showed 7% complete response and 15% overall response rate.1 However, due to its severe toxicities, such as vascular leak syndrome, pulmonary edema, and cardiac toxicity, that required inpatient administration, it has limited use. After the discoveries of immune checkpoint inhibitors (CPI), the treatment landscape of mRCC has rapidly evolved. Different combinations of CPI or with tyrosine kinase inhibitors (TKI) have been approved for first-line treatment. Despite that, achieving a durable response or overcoming resistance to CPI therapy is an unmet medical need. Revisiting IL-2 therapy and combining with CPI may overcome this and achieve better and more durable responses.

     Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist that has been shown to increase tumor-infiltrating lymphocytes (TIL), T-cell clonality and PD-1 expression2,3 (Figure 1). With its prodrug design, BEMPEG achieves rapid and sustained activation of the IL-2 pathway, and minimizes toxicity vs native IL-2 allowing for administration in an outpatient setting.2 Additionally, BEMPEG combined with the CPI nivolumab (NIVO) has been shown to convert baseline tumors from PD-L1 negative (<1%) to PD-L1 positive (≥1%).4,5 PIVOT-02 (NCT02983045) is a phase 1/2 study of BEMPEG in combination with NIVO and other anti-cancer therapies in patients with advanced solid tumors. Here we present a clinical vignette of a patient who was successfully treated with BEMPEG plus NIVO as part of the PIVOT-02 trial. Some details have been modified to protect the privacy of the individual.

Figure 1. Complete response after 18 months of treatment with BEMPEG plus NIVO

 

Case Report

Mr. F is a 50 to 55 year-old man who initially presented with sudden onset gross hematuria and was found to have a 7cm right renal mass. He underwent laparoscopic right radical nephrectomy and pathology revealed clear cell RCC, pT3a N0 M0, Fuhrman grade 2. He was initially treated on a phase 2 randomized single-blind study of Vitespen (HSPPC-96, Oncophage) for immune response assessment following treatment of patients with resectable RCC at intermediate risk for recurrence. He was followed up with CT chest, abdomen, and pelvis every 3, then 6 and 12 months.

     He did not have any evidence of recurrence until 6 years after the nephrectomy, when restaging CT showed a 2 x 3cm hypervascular lesion at the pancreatic tail and multiple subcentimeter bilateral pulmonary nodules concerning for metastasis. Endoscopic ultrasound-guided fine-needle aspiration of the pancreas lesion showed metastatic clear cell RCC. Based on the International Metastatic RCC Database Consortium (IMDC) risk strati- fication, he was categorized as having favorable-risk disease. Mr. F enrolled on the PIVOT-02 trial. His PD-L1 status at baseline was PD-L1 negative, and his initial baseline SLD was 55mm. The patient was enrolled during the dose escalation phase, where he received BEMPEG 0.003mg/kg and NIVO 240mg every 2 weeks. After 8 months, his dose of BEMPEG was increased to the recommended Phase 2 dose, 0.006mg/kg, and the NIVO increased to 360 mg every 3 weeks. At week 16, the patient achieved a 35% reduction in SLD from baseline (55 to 35). He achieved a complete response after 18 months and completed two years, a total of 40 cycles, of treatment in Q1-2019 (Figure 2).

     The patient did not experience any grade 2 or higher adverse events (AEs) during his therapy, and he remains physically active and asymptomatic from his cancer.

 

Figure 2. BEMPEG (NKTR-214) preferentially activates IL2Rbg and provides CD8 T and  NK cells
expansion and activation (adapted from Charych D et al.
) On small devices, please view on a larger screen.

 

Discussion

In the above clinical vignette, we described a patient who had a complete response with BEMPEG plus NIVO without any serious side effects. There are preclinical data and phase I BEMPEG monotherapy data6,3 supporting these findings and explaining the rationale of the PIVOT-02 trial. Earlier studies have shown that high concentrations of IL-2 cause CD8+ effector T-cell growth and activation, however low concentrations of Tregs.7 This pleiotropic effect is due to IL-2 receptor components and binding properties. IL-2Rabg, the low-affinity IL-2 receptor mostly expressed on CD8+ T cells and NK cells; the high-affinity IL-2Rabg, a heterotrimeric receptor expressed on Tregs.

    The IL-2 component of BEMPEG was specifically engineered to have preferential binding to IL-2Rabg. This provides preferential activation and expansion of CD8+ T and NK cells over Tregs in the tumor microenvironment, potentially explaining improved efficacy. There are six lysine residues on IL-2 conjugated to PEG chains as part of the BEMPEG compound. Because of PEGylation the compound is initially inactive and slowly releases PEG chains after infusion. 2-PEG-IL-2 and 1-PEG-IL-2 are the most active versions (Figure 2).3,4 In contrast to the traditional IL-2 infusion, immediate high concentrations, and related toxicity, the PEGylation allows time for tissue distribution, potentially decreasing toxicity and allowing for outpatient administration.

     The first-in-human study of BEMPEG monotherapy (the EXCEL study), assessing safety and tolerability enrolled 28 patients including 15 RCC, 7 melanoma and 6 other tumors. Patients were treated with BEMPEG every 2 or 3 weeks at different doses, 0.003mg/kg, 0.006mg/kg, 0.009mg/kg and 0.012mg/kg. The most common side effects were fatigue (71%), flu-like symptoms (68%), pruritus (64%), hypotension (57%), rash (50%), decreased appetite (46%), and arthralgia and cough (each 32%). 5 of 28 (18%) patients developed grade 3 hypotension, which was managed with IV fluids, and patients continued the treatment. After hydration guidelines were implemented, no patients experienced Grade 3 or greater AEs for hypotension. One patient discontinued the treatment due to infusion-related reaction at 0.009mg/kg. Overall, BEMPEG had a favorable safety profile, and 0.006mg/kg dose recommended for further studies. Biomarker analysis demonstrated the proliferation of CD4+, CD8+ T cells and NK cells in the peripheral blood and increased the expansion of CD8+ T cell and NK cells in the tumor. There was a transient increase in the Treg population in peripheral blood, but not in the tumor. Notably, there was an increased amount of CD8+ and PD-1+ T cells both in peripheral blood and in the tumor.3

     These preclinical and clinical studies demonstrating BEMPEG activity of increasing effector immune cell infiltration and PD-1+ T cells in the tumor microenvironment led to the Phase 1/2 PIVOT-02 trial evaluating the safety and efficacy of BEMPEG in combination with NIVO in advanced solid tumors. Based on the dose-esclation phase data, the recommended phase 2 dose is 0.006mg/kg and 360mg nivolumab IV every 3 weeks. This q3w administration of BEMPEG allows for a new generation of antigen specific T cells without leading to exhaustion. The expansion cohort includes 5 different tumor types, including RCC, melanoma, NSCLC, urothelial and triple-negative breast cancer. Preliminary results from 38 untreated metastatic melanoma patients showed 53% ORR and CR rate of 34%, which was durable and deepened over time.4 Our patient was also observed to have a deepening of response over time and was able to achieve a complete response with minimal side effects (Figure 2). It is also interesting that our patient had a similar response to that which was seen in the patients with RCC who were anti–PD-1 treatment-naïve, who ended the dose escalation (BEMPEG) with stable disease and within, 1 month started NIVO and experienced rapid tumor reductions, resulting in partial responses.3 Our patient also supports this prior hypothesis that BEMPEG may have conditioned the TME by expanding activated TILs, thereby potentially providing synergy with therapies that block inhibitory signals, such as PD-1/PD-L1.3

     The biomarker analysis confirmed the prior observation of effector T cell clonal expansion in tumor microenvironment and conversion of PD-L1 negative tumor to PD-L1 positive tumor.4,8 Similar findings were observed in the preliminary analysis of 34 metastatic urothelial cancer patients treated in this trial. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of patients, and 8.8% discontinued due to TRAEs. 6/10 (60%) PD-L1 negative tumor at baseline converted to PD-L1+ at week 3.5  Phase 2 part of the PIVOT-02 trial continues recruiting patients and final results are pending. Based on the above mentioned promising preliminary data, PIVOT-09, the Phase 3 study of BEMPEG in combination with NIVO compared with the investigator’s choice of a TKI therapy (either sunitinib or cabozantinib monotherapy) for advanced  mRCC started recruiting in December 2018.

 

Conclusion

In conclusion, we presented a patient with mRCC who achieved a deepening and complete response with BEMPEG plus NIVO and summarized the preclinical and clinical data related to BEMPEG. PIVOT-02 and PIVOT-09 are ongoing studies; the results of these studies potentially will provide a novel treatment combination for patients and further improve outcomes of patients with mRCC.

 

References

1. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–5458.

2. Charych D, Khalili S, Dixit V, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of BEMPEG, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One. 2017;12(7):5451–5458.

3. Bentebibel S-E, Hurwitz ME, Bernatchex C, et al. A first-in-human study and biomarker analysis of BEMPEG, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9(6):711–721

4. Diab A, et al. Clinical activity of BEMPEG Plus NIVO in previously untreated patients with metastatic melanoma: updated results from the phase 1/2 PIVOT-02 study. J Immunother Cancer. 2019;7(suppl 1): O35. (Presented at SITC 2019).

5. Siefker-Radtke AO, Fishman MN, Vasant Balar A, et al. BEMPEG+ nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol. 2019;37:388.

6. Charych DH, Hoch U, Langowski JL, et al. BEMPEG, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clin Cancer Res. 2016 Feb 1;22(3):680-90.

7. Boyman O, Kovar M, Rubinstein MP, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311(5769):1924–1927.

8. Hurwitz M, et al. J Clin Oncol. 2019;37(7 suppl): 2623. KCJ

 

 

 

 

Revisiting IL-2 Therapy in Renal Cell Carcinoma: 
A Case Report of a Patient Treated With Pegylated IL-2, Bempegaldesleukin (NKTR-214)
 ﷯ Department of Genitourinary Medical Oncology 
Division of Cancer Medicine 
MD Anderson Cancer Center, 
Houston, Texas
 Keywords: IL-2 therapy, nivolumab, bempegaldesleukin, immune checkpoint inhibitors, renal cell carcinoma, combination therapy. Corresponding Author: Nizar M. Tannir, MD, FACP, Ransom Horne, Jr., Professor of Cancer Research, Professor and Chair ad interim. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, 1515 Holcomb Blvd., Unit 1374, Houston, TX 77030-4009 Email: ntannir@mdanderson.org This cohort in PIVOT-02 is ongoing and full data analyses for the cohort are not yet available. Therefore, this patient case should be interpreted with caution. 
 Abstract IL-2 is a well-known stimulatory cytokine involved in differentiation and activation of T-cells and natural killer (NK) cells. FDA approved high-dose IL-2, aldesleukin for the treatment of metastatic renal cell carcinoma (mRCC) in 1992 based on the phase 2 trial that showed 7% complete response and 15% overall response rate.1 However, due to its severe toxicities, such as vascular leak syndrome, pulmonary edema, and cardiac toxicity, that required inpatient administration, it has limited use. After the discoveries of immune checkpoint inhibitors (CPI), the treatment landscape of mRCC has rapidly evolved. Different combinations of CPI or with tyrosine kinase inhibitors (TKI) have been approved for first-line treatment. Despite that, achieving a durable response or overcoming resistance to CPI therapy is an unmet medical need. Revisiting IL-2 therapy and combining with CPI may overcome this and achieve better and more durable responses. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist that has been shown to increase tumor-infiltrating lymphocytes (TIL), T-cell clonality and PD-1 expression2,3 (Figure 1). With its prodrug design, BEMPEG achieves rapid and sustained activation of the IL-2 pathway, and minimizes toxicity vs native IL-2 allowing for administration in an outpatient setting.2 Additionally, BEMPEG combined with the CPI nivolumab (NIVO) has been shown to convert baseline tumors from PD-L1 negative (<1%) to PD-L1 positive (≥1%).4,5 PIVOT-02 (NCT02983045) is a phase 1/2 study of BEMPEG in combination with NIVO and other anti-cancer therapies in patients with advanced solid tumors. Here we present a clinical vignette of a patient who was successfully treated with BEMPEG plus NIVO as part of the PIVOT-02 trial. Some details have been modified to protect the privacy of the individual. 
 ﷯ Figure 1. Complete response after 18 months of treatment with BEMPEG plus NIVO Case Report Mr. F is a 50 to 55 year-old man who initially presented with sudden onset gross hematuria and was found to have a 7cm right renal mass. He underwent laparoscopic right radical nephrectomy and pathology revealed clear cell RCC, pT3a N0 M0, Fuhrman grade 2. He was initially treated on a phase 2 randomized single-blind study of Vitespen (HSPPC-96, Oncophage) for immune response assessment following treatment of patients with resectable RCC at intermediate risk for recurrence. He was followed up with CT chest, abdomen, and pelvis every 3, then 6 and 12 months. He did not have any evidence of recurrence until 6 years after the nephrectomy, when restaging CT showed a 2 x 3cm hypervascular lesion at the pancreatic tail and multiple subcentimeter bilateral pulmonary nodules concerning for metastasis. Endoscopic ultrasound-guided fine-needle aspiration of the pancreas lesion showed metastatic clear cell RCC. Based on the International Metastatic RCC Database Consortium (IMDC) risk strati- fication, he was categorized as having favorable-risk disease. Mr. F enrolled on the PIVOT-02 trial. His PD-L1 status at baseline was PD-L1 negative, and his initial baseline SLD was 55mm. The patient was enrolled during the dose escalation phase, where he received BEMPEG 0.003mg/kg and NIVO 240mg every 2 weeks. After 8 months, his dose of BEMPEG was increased to the recommended Phase 2 dose, 0.006mg/kg, and the NIVO increased to 360 mg every 3 weeks. At week 16, the patient achieved a 35% reduction in SLD from baseline (55 to 35). He achieved a complete response after 18 months and completed two years, a total of 40 cycles, of treatment in Q1-2019 (Figure 2). The patient did not experience any grade 2 or higher adverse events (AEs) during his therapy, and he remains physically active and asymptomatic from his cancer. ﷯ Figure 2. BEMPEG (NKTR-214) preferentially activates IL2Rbg and provides CD8 T and NK cells 
expansion and activation (adapted from Charych D et al.) On small devices, please view on a larger screen. Discussion In the above clinical vignette, we described a patient who had a complete response with BEMPEG plus NIVO without any serious side effects. There are preclinical data and phase I BEMPEG monotherapy data6,3 supporting these findings and explaining the rationale of the PIVOT-02 trial. Earlier studies have shown that high concentrations of IL-2 cause CD8+ effector T-cell growth and activation, however low concentrations of Tregs.7 This pleiotropic effect is due to IL-2 receptor components and binding properties. IL-2Rabg, the low-affinity IL-2 receptor mostly expressed on CD8+ T cells and NK cells; the high-affinity IL-2Rabg, a heterotrimeric receptor expressed on Tregs. The IL-2 component of BEMPEG was specifically engineered to have preferential binding to IL-2Rabg. This provides preferential activation and expansion of CD8+ T and NK cells over Tregs in the tumor microenvironment, potentially explaining improved efficacy. There are six lysine residues on IL-2 conjugated to PEG chains as part of the BEMPEG compound. Because of PEGylation the compound is initially inactive and slowly releases PEG chains after infusion. 2-PEG-IL-2 and 1-PEG-IL-2 are the most active versions (Figure 2).3,4 In contrast to the traditional IL-2 infusion, immediate high concentrations, and related toxicity, the PEGylation allows time for tissue distribution, potentially decreasing toxicity and allowing for outpatient administration. The first-in-human study of BEMPEG monotherapy (the EXCEL study), assessing safety and tolerability enrolled 28 patients including 15 RCC, 7 melanoma and 6 other tumors. Patients were treated with BEMPEG every 2 or 3 weeks at different doses, 0.003mg/kg, 0.006mg/kg, 0.009mg/kg and 0.012mg/kg. The most common side effects were fatigue (71%), flu-like symptoms (68%), pruritus (64%), hypotension (57%), rash (50%), decreased appetite (46%), and arthralgia and cough (each 32%). 5 of 28 (18%) patients developed grade 3 hypotension, which was managed with IV fluids, and patients continued the treatment. After hydration guidelines were implemented, no patients experienced Grade 3 or greater AEs for hypotension. One patient discontinued the treatment due to infusion-related reaction at 0.009mg/kg. Overall, BEMPEG had a favorable safety profile, and 0.006mg/kg dose recommended for further studies. Biomarker analysis demonstrated the proliferation of CD4+, CD8+ T cells and NK cells in the peripheral blood and increased the expansion of CD8+ T cell and NK cells in the tumor. There was a transient increase in the Treg population in peripheral blood, but not in the tumor. Notably, there was an increased amount of CD8+ and PD-1+ T cells both in peripheral blood and in the tumor.3 These preclinical and clinical studies demonstrating BEMPEG activity of increasing effector immune cell infiltration and PD-1+ T cells in the tumor microenvironment led to the Phase 1/2 PIVOT-02 trial evaluating the safety and efficacy of BEMPEG in combination with NIVO in advanced solid tumors. Based on the dose-esclation phase data, the recommended phase 2 dose is 0.006mg/kg and 360mg nivolumab IV every 3 weeks. This q3w administration of BEMPEG allows for a new generation of antigen specific T cells without leading to exhaustion. The expansion cohort includes 5 different tumor types, including RCC, melanoma, NSCLC, urothelial and triple-negative breast cancer. Preliminary results from 38 untreated metastatic melanoma patients showed 53% ORR and CR rate of 34%, which was durable and deepened over time.4 Our patient was also observed to have a deepening of response over time and was able to achieve a complete response with minimal side effects (Figure 2). It is also interesting that our patient had a similar response to that which was seen in the patients with RCC who were anti–PD-1 treatment-naïve, who ended the dose escalation (BEMPEG) with stable disease and within, 1 month started NIVO and experienced rapid tumor reductions, resulting in partial responses.3 Our patient also supports this prior hypothesis that BEMPEG may have conditioned the TME by expanding activated TILs, thereby potentially providing synergy with therapies that block inhibitory signals, such as PD-1/PD-L1.3 The biomarker analysis confirmed the prior observation of effector T cell clonal expansion in tumor microenvironment and conversion of PD-L1 negative tumor to PD-L1 positive tumor.4,8 Similar findings were observed in the preliminary analysis of 34 metastatic urothelial cancer patients treated in this trial. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of patients, and 8.8% discontinued due to TRAEs. 6/10 (60%) PD-L1 negative tumor at baseline converted to PD-L1+ at week 3.5 Phase 2 part of the PIVOT-02 trial continues recruiting patients and final results are pending. Based on the above mentioned promising preliminary data, PIVOT-09, the Phase 3 study of BEMPEG in combination with NIVO compared with the investigator’s choice of a TKI therapy (either sunitinib or cabozantinib monotherapy) for advanced mRCC started recruiting in December 2018. Conclusion In conclusion, we presented a patient with mRCC who achieved a deepening and complete response with BEMPEG plus NIVO and summarized the preclinical and clinical data related to BEMPEG. PIVOT-02 and PIVOT-09 are ongoing studies; the results of these studies potentially will provide a novel treatment combination for patients and further improve outcomes of patients with mRCC. References 1. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–5458. 2. Charych D, Khalili S, Dixit V, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of BEMPEG, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One. 2017;12(7):5451–5458. 3. Bentebibel S-E, Hurwitz ME, Bernatchex C, et al. A first-in-human study and biomarker analysis of BEMPEG, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9(6):711–721 4. Diab A, et al. Clinical activity of BEMPEG Plus NIVO in previously untreated patients with metastatic melanoma: updated results from the phase 1/2 PIVOT-02 study. J Immunother Cancer. 2019;7(suppl 1): O35. (Presented at SITC 2019). 5. Siefker-Radtke AO, Fishman MN, Vasant Balar A, et al. BEMPEG+ nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol. 2019;37:388. 6. Charych DH, Hoch U, Langowski JL, et al. BEMPEG, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clin Cancer Res. 2016 Feb 1;22(3):680-90. 7. Boyman O, Kovar M, Rubinstein MP, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311(5769):1924–1927. 8. Hurwitz M, et al. J Clin Oncol. 2019;37(7 suppl): 2623. KCJ

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Revisiting IL-2 Therapy in Renal Cell Carcinoma: 
A Case Report of a Patient Treated With Pegylated IL-2, Bempegaldesleukin (NKTR-214)
 ﷯ Department of Genitourinary Medical Oncology 
Division of Cancer Medicine 
MD Anderson Cancer Center, 
Houston, Texas
 Keywords: IL-2 therapy, nivolumab, bempegaldesleukin, immune checkpoint inhibitors, renal cell carcinoma, combination therapy. Corresponding Author: Nizar M. Tannir, MD, FACP, Ransom Horne, Jr., Professor of Cancer Research, Professor and Chair ad interim. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, 1515 Holcomb Blvd., Unit 1374, Houston, TX 77030-4009 Email: ntannir@mdanderson.org This cohort in PIVOT-02 is ongoing and full data analyses for the cohort are not yet available. Therefore, this patient case should be interpreted with caution. 
 Abstract IL-2 is a well-known stimulatory cytokine involved in differentiation and activation of T-cells and natural killer (NK) cells. FDA approved high-dose IL-2, aldesleukin for the treatment of metastatic renal cell carcinoma (mRCC) in 1992 based on the phase 2 trial that showed 7% complete response and 15% overall response rate.1 However, due to its severe toxicities, such as vascular leak syndrome, pulmonary edema, and cardiac toxicity, that required inpatient administration, it has limited use. After the discoveries of immune checkpoint inhibitors (CPI), the treatment landscape of mRCC has rapidly evolved. Different combinations of CPI or with tyrosine kinase inhibitors (TKI) have been approved for first-line treatment. Despite that, achieving a durable response or overcoming resistance to CPI therapy is an unmet medical need. Revisiting IL-2 therapy and combining with CPI may overcome this and achieve better and more durable responses. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist that has been shown to increase tumor-infiltrating lymphocytes (TIL), T-cell clonality and PD-1 expression2,3 (Figure 1). With its prodrug design, BEMPEG achieves rapid and sustained activation of the IL-2 pathway, and minimizes toxicity vs native IL-2 allowing for administration in an outpatient setting.2 Additionally, BEMPEG combined with the CPI nivolumab (NIVO) has been shown to convert baseline tumors from PD-L1 negative (<1%) to PD-L1 positive (≥1%).4,5 PIVOT-02 (NCT02983045) is a phase 1/2 study of BEMPEG in combination with NIVO and other anti-cancer therapies in patients with advanced solid tumors. Here we present a clinical vignette of a patient who was successfully treated with BEMPEG plus NIVO as part of the PIVOT-02 trial. Some details have been modified to protect the privacy of the individual. 
 ﷯ Figure 1. Complete response after 18 months of treatment with BEMPEG plus NIVO Case Report Mr. F is a 50 to 55 year-old man who initially presented with sudden onset gross hematuria and was found to have a 7cm right renal mass. He underwent laparoscopic right radical nephrectomy and pathology revealed clear cell RCC, pT3a N0 M0, Fuhrman grade 2. He was initially treated on a phase 2 randomized single-blind study of Vitespen (HSPPC-96, Oncophage) for immune response assessment following treatment of patients with resectable RCC at intermediate risk for recurrence. He was followed up with CT chest, abdomen, and pelvis every 3, then 6 and 12 months. He did not have any evidence of recurrence until 6 years after the nephrectomy, when restaging CT showed a 2 x 3cm hypervascular lesion at the pancreatic tail and multiple subcentimeter bilateral pulmonary nodules concerning for metastasis. Endoscopic ultrasound-guided fine-needle aspiration of the pancreas lesion showed metastatic clear cell RCC. Based on the International Metastatic RCC Database Consortium (IMDC) risk strati- fication, he was categorized as having favorable-risk disease. Mr. F enrolled on the PIVOT-02 trial. His PD-L1 status at baseline was PD-L1 negative, and his initial baseline SLD was 55mm. The patient was enrolled during the dose escalation phase, where he received BEMPEG 0.003mg/kg and NIVO 240mg every 2 weeks. After 8 months, his dose of BEMPEG was increased to the recommended Phase 2 dose, 0.006mg/kg, and the NIVO increased to 360 mg every 3 weeks. At week 16, the patient achieved a 35% reduction in SLD from baseline (55 to 35). He achieved a complete response after 18 months and completed two years, a total of 40 cycles, of treatment in Q1-2019 (Figure 2). The patient did not experience any grade 2 or higher adverse events (AEs) during his therapy, and he remains physically active and asymptomatic from his cancer. ﷯ Figure 2. BEMPEG (NKTR-214) preferentially activates IL2Rbg and provides CD8 T and NK cells 
expansion and activation (adapted from Charych D et al.) On small devices, please view on a larger screen. Discussion In the above clinical vignette, we described a patient who had a complete response with BEMPEG plus NIVO without any serious side effects. There are preclinical data and phase I BEMPEG monotherapy data6,3 supporting these findings and explaining the rationale of the PIVOT-02 trial. Earlier studies have shown that high concentrations of IL-2 cause CD8+ effector T-cell growth and activation, however low concentrations of Tregs.7 This pleiotropic effect is due to IL-2 receptor components and binding properties. IL-2Rabg, the low-affinity IL-2 receptor mostly expressed on CD8+ T cells and NK cells; the high-affinity IL-2Rabg, a heterotrimeric receptor expressed on Tregs. The IL-2 component of BEMPEG was specifically engineered to have preferential binding to IL-2Rabg. This provides preferential activation and expansion of CD8+ T and NK cells over Tregs in the tumor microenvironment, potentially explaining improved efficacy. There are six lysine residues on IL-2 conjugated to PEG chains as part of the BEMPEG compound. Because of PEGylation the compound is initially inactive and slowly releases PEG chains after infusion. 2-PEG-IL-2 and 1-PEG-IL-2 are the most active versions (Figure 2).3,4 In contrast to the traditional IL-2 infusion, immediate high concentrations, and related toxicity, the PEGylation allows time for tissue distribution, potentially decreasing toxicity and allowing for outpatient administration. The first-in-human study of BEMPEG monotherapy (the EXCEL study), assessing safety and tolerability enrolled 28 patients including 15 RCC, 7 melanoma and 6 other tumors. Patients were treated with BEMPEG every 2 or 3 weeks at different doses, 0.003mg/kg, 0.006mg/kg, 0.009mg/kg and 0.012mg/kg. The most common side effects were fatigue (71%), flu-like symptoms (68%), pruritus (64%), hypotension (57%), rash (50%), decreased appetite (46%), and arthralgia and cough (each 32%). 5 of 28 (18%) patients developed grade 3 hypotension, which was managed with IV fluids, and patients continued the treatment. After hydration guidelines were implemented, no patients experienced Grade 3 or greater AEs for hypotension. One patient discontinued the treatment due to infusion-related reaction at 0.009mg/kg. Overall, BEMPEG had a favorable safety profile, and 0.006mg/kg dose recommended for further studies. Biomarker analysis demonstrated the proliferation of CD4+, CD8+ T cells and NK cells in the peripheral blood and increased the expansion of CD8+ T cell and NK cells in the tumor. There was a transient increase in the Treg population in peripheral blood, but not in the tumor. Notably, there was an increased amount of CD8+ and PD-1+ T cells both in peripheral blood and in the tumor.3 These preclinical and clinical studies demonstrating BEMPEG activity of increasing effector immune cell infiltration and PD-1+ T cells in the tumor microenvironment led to the Phase 1/2 PIVOT-02 trial evaluating the safety and efficacy of BEMPEG in combination with NIVO in advanced solid tumors. Based on the dose-esclation phase data, the recommended phase 2 dose is 0.006mg/kg and 360mg nivolumab IV every 3 weeks. This q3w administration of BEMPEG allows for a new generation of antigen specific T cells without leading to exhaustion. The expansion cohort includes 5 different tumor types, including RCC, melanoma, NSCLC, urothelial and triple-negative breast cancer. Preliminary results from 38 untreated metastatic melanoma patients showed 53% ORR and CR rate of 34%, which was durable and deepened over time.4 Our patient was also observed to have a deepening of response over time and was able to achieve a complete response with minimal side effects (Figure 2). It is also interesting that our patient had a similar response to that which was seen in the patients with RCC who were anti–PD-1 treatment-naïve, who ended the dose escalation (BEMPEG) with stable disease and within, 1 month started NIVO and experienced rapid tumor reductions, resulting in partial responses.3 Our patient also supports this prior hypothesis that BEMPEG may have conditioned the TME by expanding activated TILs, thereby potentially providing synergy with therapies that block inhibitory signals, such as PD-1/PD-L1.3 The biomarker analysis confirmed the prior observation of effector T cell clonal expansion in tumor microenvironment and conversion of PD-L1 negative tumor to PD-L1 positive tumor.4,8 Similar findings were observed in the preliminary analysis of 34 metastatic urothelial cancer patients treated in this trial. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of patients, and 8.8% discontinued due to TRAEs. 6/10 (60%) PD-L1 negative tumor at baseline converted to PD-L1+ at week 3.5 Phase 2 part of the PIVOT-02 trial continues recruiting patients and final results are pending. Based on the above mentioned promising preliminary data, PIVOT-09, the Phase 3 study of BEMPEG in combination with NIVO compared with the investigator’s choice of a TKI therapy (either sunitinib or cabozantinib monotherapy) for advanced mRCC started recruiting in December 2018. Conclusion In conclusion, we presented a patient with mRCC who achieved a deepening and complete response with BEMPEG plus NIVO and summarized the preclinical and clinical data related to BEMPEG. PIVOT-02 and PIVOT-09 are ongoing studies; the results of these studies potentially will provide a novel treatment combination for patients and further improve outcomes of patients with mRCC. References 1. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–5458. 2. Charych D, Khalili S, Dixit V, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of BEMPEG, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One. 2017;12(7):5451–5458. 3. Bentebibel S-E, Hurwitz ME, Bernatchex C, et al. A first-in-human study and biomarker analysis of BEMPEG, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9(6):711–721 4. Diab A, et al. Clinical activity of BEMPEG Plus NIVO in previously untreated patients with metastatic melanoma: updated results from the phase 1/2 PIVOT-02 study. J Immunother Cancer. 2019;7(suppl 1): O35. (Presented at SITC 2019). 5. Siefker-Radtke AO, Fishman MN, Vasant Balar A, et al. BEMPEG+ nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol. 2019;37:388. 6. Charych DH, Hoch U, Langowski JL, et al. BEMPEG, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clin Cancer Res. 2016 Feb 1;22(3):680-90. 7. Boyman O, Kovar M, Rubinstein MP, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311(5769):1924–1927. 8. Hurwitz M, et al. J Clin Oncol. 2019;37(7 suppl): 2623. KCJ
Revisiting IL-2 Therapy in Renal Cell Carcinoma: 
A Case Report of a Patient Treated With Pegylated IL-2, Bempegaldesleukin (NKTR-214)
 ﷯ Department of Genitourinary Medical Oncology 
Division of Cancer Medicine 
MD Anderson Cancer Center, 
Houston, Texas
 Keywords: IL-2 therapy, nivolumab, bempegaldesleukin, immune checkpoint inhibitors, renal cell carcinoma, combination therapy. Corresponding Author: Nizar M. Tannir, MD, FACP, Ransom Horne, Jr., Professor of Cancer Research, Professor and Chair ad interim. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, 1515 Holcomb Blvd., Unit 1374, Houston, TX 77030-4009 Email: ntannir@mdanderson.org This cohort in PIVOT-02 is ongoing and full data analyses for the cohort are not yet available. Therefore, this patient case should be interpreted with caution. 
 Abstract IL-2 is a well-known stimulatory cytokine involved in differentiation and activation of T-cells and natural killer (NK) cells. FDA approved high-dose IL-2, aldesleukin for the treatment of metastatic renal cell carcinoma (mRCC) in 1992 based on the phase 2 trial that showed 7% complete response and 15% overall response rate.1 However, due to its severe toxicities, such as vascular leak syndrome, pulmonary edema, and cardiac toxicity, that required inpatient administration, it has limited use. After the discoveries of immune checkpoint inhibitors (CPI), the treatment landscape of mRCC has rapidly evolved. Different combinations of CPI or with tyrosine kinase inhibitors (TKI) have been approved for first-line treatment. Despite that, achieving a durable response or overcoming resistance to CPI therapy is an unmet medical need. Revisiting IL-2 therapy and combining with CPI may overcome this and achieve better and more durable responses. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist that has been shown to increase tumor-infiltrating lymphocytes (TIL), T-cell clonality and PD-1 expression2,3 (Figure 1). With its prodrug design, BEMPEG achieves rapid and sustained activation of the IL-2 pathway, and minimizes toxicity vs native IL-2 allowing for administration in an outpatient setting.2 Additionally, BEMPEG combined with the CPI nivolumab (NIVO) has been shown to convert baseline tumors from PD-L1 negative (<1%) to PD-L1 positive (≥1%).4,5 PIVOT-02 (NCT02983045) is a phase 1/2 study of BEMPEG in combination with NIVO and other anti-cancer therapies in patients with advanced solid tumors. Here we present a clinical vignette of a patient who was successfully treated with BEMPEG plus NIVO as part of the PIVOT-02 trial. Some details have been modified to protect the privacy of the individual. 
 ﷯ Figure 1. Complete response after 18 months of treatment with BEMPEG plus NIVO Case Report Mr. F is a 50 to 55 year-old man who initially presented with sudden onset gross hematuria and was found to have a 7cm right renal mass. He underwent laparoscopic right radical nephrectomy and pathology revealed clear cell RCC, pT3a N0 M0, Fuhrman grade 2. He was initially treated on a phase 2 randomized single-blind study of Vitespen (HSPPC-96, Oncophage) for immune response assessment following treatment of patients with resectable RCC at intermediate risk for recurrence. He was followed up with CT chest, abdomen, and pelvis every 3, then 6 and 12 months. He did not have any evidence of recurrence until 6 years after the nephrectomy, when restaging CT showed a 2 x 3cm hypervascular lesion at the pancreatic tail and multiple subcentimeter bilateral pulmonary nodules concerning for metastasis. Endoscopic ultrasound-guided fine-needle aspiration of the pancreas lesion showed metastatic clear cell RCC. Based on the International Metastatic RCC Database Consortium (IMDC) risk strati- fication, he was categorized as having favorable-risk disease. Mr. F enrolled on the PIVOT-02 trial. His PD-L1 status at baseline was PD-L1 negative, and his initial baseline SLD was 55mm. The patient was enrolled during the dose escalation phase, where he received BEMPEG 0.003mg/kg and NIVO 240mg every 2 weeks. After 8 months, his dose of BEMPEG was increased to the recommended Phase 2 dose, 0.006mg/kg, and the NIVO increased to 360 mg every 3 weeks. At week 16, the patient achieved a 35% reduction in SLD from baseline (55 to 35). He achieved a complete response after 18 months and completed two years, a total of 40 cycles, of treatment in Q1-2019 (Figure 2). The patient did not experience any grade 2 or higher adverse events (AEs) during his therapy, and he remains physically active and asymptomatic from his cancer. ﷯ Figure 2. BEMPEG (NKTR-214) preferentially activates IL2Rbg and provides CD8 T and NK cells 
expansion and activation (adapted from Charych D et al.) On small devices, please view on a larger screen. Discussion In the above clinical vignette, we described a patient who had a complete response with BEMPEG plus NIVO without any serious side effects. There are preclinical data and phase I BEMPEG monotherapy data6,3 supporting these findings and explaining the rationale of the PIVOT-02 trial. Earlier studies have shown that high concentrations of IL-2 cause CD8+ effector T-cell growth and activation, however low concentrations of Tregs.7 This pleiotropic effect is due to IL-2 receptor components and binding properties. IL-2Rabg, the low-affinity IL-2 receptor mostly expressed on CD8+ T cells and NK cells; the high-affinity IL-2Rabg, a heterotrimeric receptor expressed on Tregs. The IL-2 component of BEMPEG was specifically engineered to have preferential binding to IL-2Rabg. This provides preferential activation and expansion of CD8+ T and NK cells over Tregs in the tumor microenvironment, potentially explaining improved efficacy. There are six lysine residues on IL-2 conjugated to PEG chains as part of the BEMPEG compound. Because of PEGylation the compound is initially inactive and slowly releases PEG chains after infusion. 2-PEG-IL-2 and 1-PEG-IL-2 are the most active versions (Figure 2).3,4 In contrast to the traditional IL-2 infusion, immediate high concentrations, and related toxicity, the PEGylation allows time for tissue distribution, potentially decreasing toxicity and allowing for outpatient administration. The first-in-human study of BEMPEG monotherapy (the EXCEL study), assessing safety and tolerability enrolled 28 patients including 15 RCC, 7 melanoma and 6 other tumors. Patients were treated with BEMPEG every 2 or 3 weeks at different doses, 0.003mg/kg, 0.006mg/kg, 0.009mg/kg and 0.012mg/kg. The most common side effects were fatigue (71%), flu-like symptoms (68%), pruritus (64%), hypotension (57%), rash (50%), decreased appetite (46%), and arthralgia and cough (each 32%). 5 of 28 (18%) patients developed grade 3 hypotension, which was managed with IV fluids, and patients continued the treatment. After hydration guidelines were implemented, no patients experienced Grade 3 or greater AEs for hypotension. One patient discontinued the treatment due to infusion-related reaction at 0.009mg/kg. Overall, BEMPEG had a favorable safety profile, and 0.006mg/kg dose recommended for further studies. Biomarker analysis demonstrated the proliferation of CD4+, CD8+ T cells and NK cells in the peripheral blood and increased the expansion of CD8+ T cell and NK cells in the tumor. There was a transient increase in the Treg population in peripheral blood, but not in the tumor. Notably, there was an increased amount of CD8+ and PD-1+ T cells both in peripheral blood and in the tumor.3 These preclinical and clinical studies demonstrating BEMPEG activity of increasing effector immune cell infiltration and PD-1+ T cells in the tumor microenvironment led to the Phase 1/2 PIVOT-02 trial evaluating the safety and efficacy of BEMPEG in combination with NIVO in advanced solid tumors. Based on the dose-esclation phase data, the recommended phase 2 dose is 0.006mg/kg and 360mg nivolumab IV every 3 weeks. This q3w administration of BEMPEG allows for a new generation of antigen specific T cells without leading to exhaustion. The expansion cohort includes 5 different tumor types, including RCC, melanoma, NSCLC, urothelial and triple-negative breast cancer. Preliminary results from 38 untreated metastatic melanoma patients showed 53% ORR and CR rate of 34%, which was durable and deepened over time.4 Our patient was also observed to have a deepening of response over time and was able to achieve a complete response with minimal side effects (Figure 2). It is also interesting that our patient had a similar response to that which was seen in the patients with RCC who were anti–PD-1 treatment-naïve, who ended the dose escalation (BEMPEG) with stable disease and within, 1 month started NIVO and experienced rapid tumor reductions, resulting in partial responses.3 Our patient also supports this prior hypothesis that BEMPEG may have conditioned the TME by expanding activated TILs, thereby potentially providing synergy with therapies that block inhibitory signals, such as PD-1/PD-L1.3 The biomarker analysis confirmed the prior observation of effector T cell clonal expansion in tumor microenvironment and conversion of PD-L1 negative tumor to PD-L1 positive tumor.4,8 Similar findings were observed in the preliminary analysis of 34 metastatic urothelial cancer patients treated in this trial. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of patients, and 8.8% discontinued due to TRAEs. 6/10 (60%) PD-L1 negative tumor at baseline converted to PD-L1+ at week 3.5 Phase 2 part of the PIVOT-02 trial continues recruiting patients and final results are pending. Based on the above mentioned promising preliminary data, PIVOT-09, the Phase 3 study of BEMPEG in combination with NIVO compared with the investigator’s choice of a TKI therapy (either sunitinib or cabozantinib monotherapy) for advanced mRCC started recruiting in December 2018. Conclusion In conclusion, we presented a patient with mRCC who achieved a deepening and complete response with BEMPEG plus NIVO and summarized the preclinical and clinical data related to BEMPEG. PIVOT-02 and PIVOT-09 are ongoing studies; the results of these studies potentially will provide a novel treatment combination for patients and further improve outcomes of patients with mRCC. References 1. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–5458. 2. Charych D, Khalili S, Dixit V, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of BEMPEG, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One. 2017;12(7):5451–5458. 3. Bentebibel S-E, Hurwitz ME, Bernatchex C, et al. A first-in-human study and biomarker analysis of BEMPEG, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9(6):711–721 4. Diab A, et al. Clinical activity of BEMPEG Plus NIVO in previously untreated patients with metastatic melanoma: updated results from the phase 1/2 PIVOT-02 study. J Immunother Cancer. 2019;7(suppl 1): O35. (Presented at SITC 2019). 5. Siefker-Radtke AO, Fishman MN, Vasant Balar A, et al. BEMPEG+ nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol. 2019;37:388. 6. Charych DH, Hoch U, Langowski JL, et al. BEMPEG, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clin Cancer Res. 2016 Feb 1;22(3):680-90. 7. Boyman O, Kovar M, Rubinstein MP, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311(5769):1924–1927. 8. Hurwitz M, et al. J Clin Oncol. 2019;37(7 suppl): 2623. KCJ
Revisiting IL-2 Therapy in Renal Cell Carcinoma: 
A Case Report of a Patient Treated With Pegylated IL-2, Bempegaldesleukin (NKTR-214)
 ﷯ Department of Genitourinary Medical Oncology 
Division of Cancer Medicine 
MD Anderson Cancer Center, 
Houston, Texas
 Keywords: IL-2 therapy, nivolumab, bempegaldesleukin, immune checkpoint inhibitors, renal cell carcinoma, combination therapy. Corresponding Author: Nizar M. Tannir, MD, FACP, Ransom Horne, Jr., Professor of Cancer Research, Professor and Chair ad interim. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, 1515 Holcomb Blvd., Unit 1374, Houston, TX 77030-4009 Email: ntannir@mdanderson.org This cohort in PIVOT-02 is ongoing and full data analyses for the cohort are not yet available. Therefore, this patient case should be interpreted with caution. 
 Abstract IL-2 is a well-known stimulatory cytokine involved in differentiation and activation of T-cells and natural killer (NK) cells. FDA approved high-dose IL-2, aldesleukin for the treatment of metastatic renal cell carcinoma (mRCC) in 1992 based on the phase 2 trial that showed 7% complete response and 15% overall response rate.1 However, due to its severe toxicities, such as vascular leak syndrome, pulmonary edema, and cardiac toxicity, that required inpatient administration, it has limited use. After the discoveries of immune checkpoint inhibitors (CPI), the treatment landscape of mRCC has rapidly evolved. Different combinations of CPI or with tyrosine kinase inhibitors (TKI) have been approved for first-line treatment. Despite that, achieving a durable response or overcoming resistance to CPI therapy is an unmet medical need. Revisiting IL-2 therapy and combining with CPI may overcome this and achieve better and more durable responses. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist that has been shown to increase tumor-infiltrating lymphocytes (TIL), T-cell clonality and PD-1 expression2,3 (Figure 1). With its prodrug design, BEMPEG achieves rapid and sustained activation of the IL-2 pathway, and minimizes toxicity vs native IL-2 allowing for administration in an outpatient setting.2 Additionally, BEMPEG combined with the CPI nivolumab (NIVO) has been shown to convert baseline tumors from PD-L1 negative (<1%) to PD-L1 positive (≥1%).4,5 PIVOT-02 (NCT02983045) is a phase 1/2 study of BEMPEG in combination with NIVO and other anti-cancer therapies in patients with advanced solid tumors. Here we present a clinical vignette of a patient who was successfully treated with BEMPEG plus NIVO as part of the PIVOT-02 trial. Some details have been modified to protect the privacy of the individual. 
 ﷯ Figure 1. Complete response after 18 months of treatment with BEMPEG plus NIVO Case Report Mr. F is a 50 to 55 year-old man who initially presented with sudden onset gross hematuria and was found to have a 7cm right renal mass. He underwent laparoscopic right radical nephrectomy and pathology revealed clear cell RCC, pT3a N0 M0, Fuhrman grade 2. He was initially treated on a phase 2 randomized single-blind study of Vitespen (HSPPC-96, Oncophage) for immune response assessment following treatment of patients with resectable RCC at intermediate risk for recurrence. He was followed up with CT chest, abdomen, and pelvis every 3, then 6 and 12 months. He did not have any evidence of recurrence until 6 years after the nephrectomy, when restaging CT showed a 2 x 3cm hypervascular lesion at the pancreatic tail and multiple subcentimeter bilateral pulmonary nodules concerning for metastasis. Endoscopic ultrasound-guided fine-needle aspiration of the pancreas lesion showed metastatic clear cell RCC. Based on the International Metastatic RCC Database Consortium (IMDC) risk strati- fication, he was categorized as having favorable-risk disease. Mr. F enrolled on the PIVOT-02 trial. His PD-L1 status at baseline was PD-L1 negative, and his initial baseline SLD was 55mm. The patient was enrolled during the dose escalation phase, where he received BEMPEG 0.003mg/kg and NIVO 240mg every 2 weeks. After 8 months, his dose of BEMPEG was increased to the recommended Phase 2 dose, 0.006mg/kg, and the NIVO increased to 360 mg every 3 weeks. At week 16, the patient achieved a 35% reduction in SLD from baseline (55 to 35). He achieved a complete response after 18 months and completed two years, a total of 40 cycles, of treatment in Q1-2019 (Figure 2). The patient did not experience any grade 2 or higher adverse events (AEs) during his therapy, and he remains physically active and asymptomatic from his cancer. ﷯ Figure 2. BEMPEG (NKTR-214) preferentially activates IL2Rbg and provides CD8 T and NK cells 
expansion and activation (adapted from Charych D et al.) On small devices, please view on a larger screen. Discussion In the above clinical vignette, we described a patient who had a complete response with BEMPEG plus NIVO without any serious side effects. There are preclinical data and phase I BEMPEG monotherapy data6,3 supporting these findings and explaining the rationale of the PIVOT-02 trial. Earlier studies have shown that high concentrations of IL-2 cause CD8+ effector T-cell growth and activation, however low concentrations of Tregs.7 This pleiotropic effect is due to IL-2 receptor components and binding properties. IL-2Rabg, the low-affinity IL-2 receptor mostly expressed on CD8+ T cells and NK cells; the high-affinity IL-2Rabg, a heterotrimeric receptor expressed on Tregs. The IL-2 component of BEMPEG was specifically engineered to have preferential binding to IL-2Rabg. This provides preferential activation and expansion of CD8+ T and NK cells over Tregs in the tumor microenvironment, potentially explaining improved efficacy. There are six lysine residues on IL-2 conjugated to PEG chains as part of the BEMPEG compound. Because of PEGylation the compound is initially inactive and slowly releases PEG chains after infusion. 2-PEG-IL-2 and 1-PEG-IL-2 are the most active versions (Figure 2).3,4 In contrast to the traditional IL-2 infusion, immediate high concentrations, and related toxicity, the PEGylation allows time for tissue distribution, potentially decreasing toxicity and allowing for outpatient administration. The first-in-human study of BEMPEG monotherapy (the EXCEL study), assessing safety and tolerability enrolled 28 patients including 15 RCC, 7 melanoma and 6 other tumors. Patients were treated with BEMPEG every 2 or 3 weeks at different doses, 0.003mg/kg, 0.006mg/kg, 0.009mg/kg and 0.012mg/kg. The most common side effects were fatigue (71%), flu-like symptoms (68%), pruritus (64%), hypotension (57%), rash (50%), decreased appetite (46%), and arthralgia and cough (each 32%). 5 of 28 (18%) patients developed grade 3 hypotension, which was managed with IV fluids, and patients continued the treatment. After hydration guidelines were implemented, no patients experienced Grade 3 or greater AEs for hypotension. One patient discontinued the treatment due to infusion-related reaction at 0.009mg/kg. Overall, BEMPEG had a favorable safety profile, and 0.006mg/kg dose recommended for further studies. Biomarker analysis demonstrated the proliferation of CD4+, CD8+ T cells and NK cells in the peripheral blood and increased the expansion of CD8+ T cell and NK cells in the tumor. There was a transient increase in the Treg population in peripheral blood, but not in the tumor. Notably, there was an increased amount of CD8+ and PD-1+ T cells both in peripheral blood and in the tumor.3 These preclinical and clinical studies demonstrating BEMPEG activity of increasing effector immune cell infiltration and PD-1+ T cells in the tumor microenvironment led to the Phase 1/2 PIVOT-02 trial evaluating the safety and efficacy of BEMPEG in combination with NIVO in advanced solid tumors. Based on the dose-esclation phase data, the recommended phase 2 dose is 0.006mg/kg and 360mg nivolumab IV every 3 weeks. This q3w administration of BEMPEG allows for a new generation of antigen specific T cells without leading to exhaustion. The expansion cohort includes 5 different tumor types, including RCC, melanoma, NSCLC, urothelial and triple-negative breast cancer. Preliminary results from 38 untreated metastatic melanoma patients showed 53% ORR and CR rate of 34%, which was durable and deepened over time.4 Our patient was also observed to have a deepening of response over time and was able to achieve a complete response with minimal side effects (Figure 2). It is also interesting that our patient had a similar response to that which was seen in the patients with RCC who were anti–PD-1 treatment-naïve, who ended the dose escalation (BEMPEG) with stable disease and within, 1 month started NIVO and experienced rapid tumor reductions, resulting in partial responses.3 Our patient also supports this prior hypothesis that BEMPEG may have conditioned the TME by expanding activated TILs, thereby potentially providing synergy with therapies that block inhibitory signals, such as PD-1/PD-L1.3 The biomarker analysis confirmed the prior observation of effector T cell clonal expansion in tumor microenvironment and conversion of PD-L1 negative tumor to PD-L1 positive tumor.4,8 Similar findings were observed in the preliminary analysis of 34 metastatic urothelial cancer patients treated in this trial. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of patients, and 8.8% discontinued due to TRAEs. 6/10 (60%) PD-L1 negative tumor at baseline converted to PD-L1+ at week 3.5 Phase 2 part of the PIVOT-02 trial continues recruiting patients and final results are pending. Based on the above mentioned promising preliminary data, PIVOT-09, the Phase 3 study of BEMPEG in combination with NIVO compared with the investigator’s choice of a TKI therapy (either sunitinib or cabozantinib monotherapy) for advanced mRCC started recruiting in December 2018. Conclusion In conclusion, we presented a patient with mRCC who achieved a deepening and complete response with BEMPEG plus NIVO and summarized the preclinical and clinical data related to BEMPEG. PIVOT-02 and PIVOT-09 are ongoing studies; the results of these studies potentially will provide a novel treatment combination for patients and further improve outcomes of patients with mRCC. References 1. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–5458. 2. Charych D, Khalili S, Dixit V, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of BEMPEG, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One. 2017;12(7):5451–5458. 3. Bentebibel S-E, Hurwitz ME, Bernatchex C, et al. A first-in-human study and biomarker analysis of BEMPEG, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9(6):711–721 4. Diab A, et al. Clinical activity of BEMPEG Plus NIVO in previously untreated patients with metastatic melanoma: updated results from the phase 1/2 PIVOT-02 study. J Immunother Cancer. 2019;7(suppl 1): O35. (Presented at SITC 2019). 5. Siefker-Radtke AO, Fishman MN, Vasant Balar A, et al. BEMPEG+ nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol. 2019;37:388. 6. Charych DH, Hoch U, Langowski JL, et al. BEMPEG, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clin Cancer Res. 2016 Feb 1;22(3):680-90. 7. Boyman O, Kovar M, Rubinstein MP, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311(5769):1924–1927. 8. Hurwitz M, et al. J Clin Oncol. 2019;37(7 suppl): 2623. KCJ
Revisiting IL-2 Therapy in Renal Cell Carcinoma: 
A Case Report of a Patient Treated With Pegylated IL-2, Bempegaldesleukin (NKTR-214)
 ﷯ Department of Genitourinary Medical Oncology 
Division of Cancer Medicine 
MD Anderson Cancer Center, 
Houston, Texas
 Keywords: IL-2 therapy, nivolumab, bempegaldesleukin, immune checkpoint inhibitors, renal cell carcinoma, combination therapy. Corresponding Author: Nizar M. Tannir, MD, FACP, Ransom Horne, Jr., Professor of Cancer Research, Professor and Chair ad interim. Department of Genitourinary Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, 1515 Holcomb Blvd., Unit 1374, Houston, TX 77030-4009 Email: ntannir@mdanderson.org This cohort in PIVOT-02 is ongoing and full data analyses for the cohort are not yet available. Therefore, this patient case should be interpreted with caution. 
 Abstract IL-2 is a well-known stimulatory cytokine involved in differentiation and activation of T-cells and natural killer (NK) cells. FDA approved high-dose IL-2, aldesleukin for the treatment of metastatic renal cell carcinoma (mRCC) in 1992 based on the phase 2 trial that showed 7% complete response and 15% overall response rate.1 However, due to its severe toxicities, such as vascular leak syndrome, pulmonary edema, and cardiac toxicity, that required inpatient administration, it has limited use. After the discoveries of immune checkpoint inhibitors (CPI), the treatment landscape of mRCC has rapidly evolved. Different combinations of CPI or with tyrosine kinase inhibitors (TKI) have been approved for first-line treatment. Despite that, achieving a durable response or overcoming resistance to CPI therapy is an unmet medical need. Revisiting IL-2 therapy and combining with CPI may overcome this and achieve better and more durable responses. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist that has been shown to increase tumor-infiltrating lymphocytes (TIL), T-cell clonality and PD-1 expression2,3 (Figure 1). With its prodrug design, BEMPEG achieves rapid and sustained activation of the IL-2 pathway, and minimizes toxicity vs native IL-2 allowing for administration in an outpatient setting.2 Additionally, BEMPEG combined with the CPI nivolumab (NIVO) has been shown to convert baseline tumors from PD-L1 negative (<1%) to PD-L1 positive (≥1%).4,5 PIVOT-02 (NCT02983045) is a phase 1/2 study of BEMPEG in combination with NIVO and other anti-cancer therapies in patients with advanced solid tumors. Here we present a clinical vignette of a patient who was successfully treated with BEMPEG plus NIVO as part of the PIVOT-02 trial. Some details have been modified to protect the privacy of the individual. 
 ﷯ Figure 1. Complete response after 18 months of treatment with BEMPEG plus NIVO Case Report Mr. F is a 50 to 55 year-old man who initially presented with sudden onset gross hematuria and was found to have a 7cm right renal mass. He underwent laparoscopic right radical nephrectomy and pathology revealed clear cell RCC, pT3a N0 M0, Fuhrman grade 2. He was initially treated on a phase 2 randomized single-blind study of Vitespen (HSPPC-96, Oncophage) for immune response assessment following treatment of patients with resectable RCC at intermediate risk for recurrence. He was followed up with CT chest, abdomen, and pelvis every 3, then 6 and 12 months. He did not have any evidence of recurrence until 6 years after the nephrectomy, when restaging CT showed a 2 x 3cm hypervascular lesion at the pancreatic tail and multiple subcentimeter bilateral pulmonary nodules concerning for metastasis. Endoscopic ultrasound-guided fine-needle aspiration of the pancreas lesion showed metastatic clear cell RCC. Based on the International Metastatic RCC Database Consortium (IMDC) risk strati- fication, he was categorized as having favorable-risk disease. Mr. F enrolled on the PIVOT-02 trial. His PD-L1 status at baseline was PD-L1 negative, and his initial baseline SLD was 55mm. The patient was enrolled during the dose escalation phase, where he received BEMPEG 0.003mg/kg and NIVO 240mg every 2 weeks. After 8 months, his dose of BEMPEG was increased to the recommended Phase 2 dose, 0.006mg/kg, and the NIVO increased to 360 mg every 3 weeks. At week 16, the patient achieved a 35% reduction in SLD from baseline (55 to 35). He achieved a complete response after 18 months and completed two years, a total of 40 cycles, of treatment in Q1-2019 (Figure 2). The patient did not experience any grade 2 or higher adverse events (AEs) during his therapy, and he remains physically active and asymptomatic from his cancer. ﷯ Figure 2. BEMPEG (NKTR-214) preferentially activates IL2Rbg and provides CD8 T and NK cells 
expansion and activation (adapted from Charych D et al.) On small devices, please view on a larger screen. Discussion In the above clinical vignette, we described a patient who had a complete response with BEMPEG plus NIVO without any serious side effects. There are preclinical data and phase I BEMPEG monotherapy data6,3 supporting these findings and explaining the rationale of the PIVOT-02 trial. Earlier studies have shown that high concentrations of IL-2 cause CD8+ effector T-cell growth and activation, however low concentrations of Tregs.7 This pleiotropic effect is due to IL-2 receptor components and binding properties. IL-2Rabg, the low-affinity IL-2 receptor mostly expressed on CD8+ T cells and NK cells; the high-affinity IL-2Rabg, a heterotrimeric receptor expressed on Tregs. The IL-2 component of BEMPEG was specifically engineered to have preferential binding to IL-2Rabg. This provides preferential activation and expansion of CD8+ T and NK cells over Tregs in the tumor microenvironment, potentially explaining improved efficacy. There are six lysine residues on IL-2 conjugated to PEG chains as part of the BEMPEG compound. Because of PEGylation the compound is initially inactive and slowly releases PEG chains after infusion. 2-PEG-IL-2 and 1-PEG-IL-2 are the most active versions (Figure 2).3,4 In contrast to the traditional IL-2 infusion, immediate high concentrations, and related toxicity, the PEGylation allows time for tissue distribution, potentially decreasing toxicity and allowing for outpatient administration. The first-in-human study of BEMPEG monotherapy (the EXCEL study), assessing safety and tolerability enrolled 28 patients including 15 RCC, 7 melanoma and 6 other tumors. Patients were treated with BEMPEG every 2 or 3 weeks at different doses, 0.003mg/kg, 0.006mg/kg, 0.009mg/kg and 0.012mg/kg. The most common side effects were fatigue (71%), flu-like symptoms (68%), pruritus (64%), hypotension (57%), rash (50%), decreased appetite (46%), and arthralgia and cough (each 32%). 5 of 28 (18%) patients developed grade 3 hypotension, which was managed with IV fluids, and patients continued the treatment. After hydration guidelines were implemented, no patients experienced Grade 3 or greater AEs for hypotension. One patient discontinued the treatment due to infusion-related reaction at 0.009mg/kg. Overall, BEMPEG had a favorable safety profile, and 0.006mg/kg dose recommended for further studies. Biomarker analysis demonstrated the proliferation of CD4+, CD8+ T cells and NK cells in the peripheral blood and increased the expansion of CD8+ T cell and NK cells in the tumor. There was a transient increase in the Treg population in peripheral blood, but not in the tumor. Notably, there was an increased amount of CD8+ and PD-1+ T cells both in peripheral blood and in the tumor.3 These preclinical and clinical studies demonstrating BEMPEG activity of increasing effector immune cell infiltration and PD-1+ T cells in the tumor microenvironment led to the Phase 1/2 PIVOT-02 trial evaluating the safety and efficacy of BEMPEG in combination with NIVO in advanced solid tumors. Based on the dose-esclation phase data, the recommended phase 2 dose is 0.006mg/kg and 360mg nivolumab IV every 3 weeks. This q3w administration of BEMPEG allows for a new generation of antigen specific T cells without leading to exhaustion. The expansion cohort includes 5 different tumor types, including RCC, melanoma, NSCLC, urothelial and triple-negative breast cancer. Preliminary results from 38 untreated metastatic melanoma patients showed 53% ORR and CR rate of 34%, which was durable and deepened over time.4 Our patient was also observed to have a deepening of response over time and was able to achieve a complete response with minimal side effects (Figure 2). It is also interesting that our patient had a similar response to that which was seen in the patients with RCC who were anti–PD-1 treatment-naïve, who ended the dose escalation (BEMPEG) with stable disease and within, 1 month started NIVO and experienced rapid tumor reductions, resulting in partial responses.3 Our patient also supports this prior hypothesis that BEMPEG may have conditioned the TME by expanding activated TILs, thereby potentially providing synergy with therapies that block inhibitory signals, such as PD-1/PD-L1.3 The biomarker analysis confirmed the prior observation of effector T cell clonal expansion in tumor microenvironment and conversion of PD-L1 negative tumor to PD-L1 positive tumor.4,8 Similar findings were observed in the preliminary analysis of 34 metastatic urothelial cancer patients treated in this trial. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of patients, and 8.8% discontinued due to TRAEs. 6/10 (60%) PD-L1 negative tumor at baseline converted to PD-L1+ at week 3.5 Phase 2 part of the PIVOT-02 trial continues recruiting patients and final results are pending. Based on the above mentioned promising preliminary data, PIVOT-09, the Phase 3 study of BEMPEG in combination with NIVO compared with the investigator’s choice of a TKI therapy (either sunitinib or cabozantinib monotherapy) for advanced mRCC started recruiting in December 2018. Conclusion In conclusion, we presented a patient with mRCC who achieved a deepening and complete response with BEMPEG plus NIVO and summarized the preclinical and clinical data related to BEMPEG. PIVOT-02 and PIVOT-09 are ongoing studies; the results of these studies potentially will provide a novel treatment combination for patients and further improve outcomes of patients with mRCC. References 1. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192(12):5451–5458. 2. Charych D, Khalili S, Dixit V, et al. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of BEMPEG, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy. PLoS One. 2017;12(7):5451–5458. 3. Bentebibel S-E, Hurwitz ME, Bernatchex C, et al. A first-in-human study and biomarker analysis of BEMPEG, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9(6):711–721 4. Diab A, et al. Clinical activity of BEMPEG Plus NIVO in previously untreated patients with metastatic melanoma: updated results from the phase 1/2 PIVOT-02 study. J Immunother Cancer. 2019;7(suppl 1): O35. (Presented at SITC 2019). 5. Siefker-Radtke AO, Fishman MN, Vasant Balar A, et al. BEMPEG+ nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol. 2019;37:388. 6. Charych DH, Hoch U, Langowski JL, et al. BEMPEG, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models. Clin Cancer Res. 2016 Feb 1;22(3):680-90. 7. Boyman O, Kovar M, Rubinstein MP, et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311(5769):1924–1927. 8. Hurwitz M, et al. J Clin Oncol. 2019;37(7 suppl): 2623. KCJ