Subcutaneous nivolumab versus intravenous nivolumab in patients with previously treated, advanced, or metastatic clear cell renal cell carcinoma

Background: Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, has demonstrated clinical efficacy across patients with different tumor types, including clear cell renal cell carcinoma (ccRCC), when administered via IV infusion. As an alternative to IV infusion, subcutaneous (SC) administration alleviates the need for IV ports, thereby lowering the risk of associated complications such as infections and phlebitis. SC formulation also reduces the time for dose preparation and administration, which may decrease overall treatment burden and reduce patient time in the clinic, benefiting patients and healthcare providers and improving overall healthcare resource utilization. SC-administered NIVO consists of NIVO co-formulated with the recombinant human hyaluronidase PH20 enzyme (NIVO + rHuPH20), which aims to increase the dispersion and absorption of NIVO within the SC space. SC NIVO + rHuPH20 was shown to be safe and well tolerated in a phase 1/2 study, warranting further investigation (Lonardi S et al. J Clin Oncol 2021;39(suppl 15):2575). Methods: CheckMate 67T is a multicenter, randomized, open-label, phase 3 study that will evaluate the noninferiority of SC NIVO + rHuPH20 versus IV NIVO in patients with advanced or metastatic ccRCC who have progressed after receiving ≤ 2 prior systemic treatment regimens. Key inclusion criteria are age ≥ 18 years, histologically confirmed advanced or metastatic ccRCC, measurable disease by RECIST v1.1 within 28 days prior to randomization, and a Karnofsky performance status ≥ 70. Key exclusion criteria are untreated symptomatic metastases to the central nervous system, other malignancy, autoimmune diseases, HIV-positive status with AIDS-defining infection within past year or current CD4 count < 350 cells/μL, other serious or uncontrolled disorders including severe, acute SARS-CoV-2 infection, and prior treatment with immune checkpoint inhibitors, other T-cell-targeting antibody drugs, or live attenuated vaccines within 30 days of first study treatment. At least 454 eligible patients will be randomized to receive SC NIVO + rHuPH20 or IV NIVO. The primary objectives are to demonstrate pharmacokinetic (PK) noninferiority of SC NIVO versus IV NIVO, as measured by time-averaged serum concentration over the first 28 days (Cavgd28) and trough serum concentration at steady state (Cminss) (co-primary endpoints). Secondary endpoints include objective response rate by blinded independent central review, additional PK parameters, safety, efficacy, and immunogenicity of SC NIVO and IV NIVO. This study is currently enrolling patients globally.

Real-word evidence in patients treated with pazopanib for advanced/metastatic renal cell carcinoma (mRCC): The APOLON study

Background: The efficacy and safety of pazopanib (PZP) have been evaluated in pivotal randomized, clinical trials Real-world evidence (RWE) is required to further assess its use, effectiveness and safety in mRCC in clinical routine practices. Methods: APOLON is a non-interventional, multicentric prospective study with mRCC patients who receive frontline PZP treatment. The study is designed to assess PZP Progression-Free Survival (PFS) (under treatment), Overall Survival (OS), Objective Response Rate (ORR) assessed by investigators, tolerability and subsequent post-pazopanib therapy sequences. Impact of COVID-19 on patient's care was also assessed. Eligible patients were recruited from Nov 2017 to Jan 2019 in 55 participant sites in France. This interim analysis presents results 30 months (mo) after last patient was enrolled in the study. Results: The 217 patients were 71.1% males, with a median age of 69.6 years and had mRCC with a favourable (27.1%), intermediate (52.1%) or poor (20.8%) IMDC risk score according to physician. ECOG-PS was 0, 1 and ≥2 in respectively 43.3%, 39% and 17.6% of patients. Metastases were mainly located in lungs (64.1%), bones (28.6%), mediastinal (18%)/abdominal (17.1%). Patients had an history of partial/total nephrectomy in 54.8% of cases and previous local treatments for metastases in 27.6%. Median PFS, assessed by investigator, was 10.5 mo (95%CI: 9-12.4), similarly in patients < 65-year-old (YO) with 11.3 mo (95%CI: 7-16.3) and in those ≥ 65 YO with 9.9 mo (95%CI: 8.9-12). When assessed according to the IMDC risk score, mPFS was 18.1 mo (95%CI: 9.9-23.3) in favourable, 11.5 mo (95%CI: 8.7-14.4) in intermediate and 6.2 mo (95%CI: 3.5-9.5) in poor mRCC. The median OS was 27.3 mo (95%CI: 24.3 - ND). Investigator-assessed ORR was 48.3% with a CR in 6 patients (3.5%) and a PR in 77 (44.8%). After a median treatment duration of 10.1 mo, 190 patients (87.6%) discontinued PZP and 67.9% received at least one post-PZP line. Second line post-PZP consisted in nivolumab (71.3%), cabozantinib (14.7%), sunitinib (7%) or other (7%). Adverse Event (AE) leading to PZP dose reduction and discontinuation were reported in 42% and 40.9% of patients and treatment-related serious AE in 22.2% of patients. No safety signal was newly identified. The impact of the Covid 19 pandemic was limited on patients' cares and study follow-up. Visits during the pandemic included 84.1% of tumour evaluation. For 29 patients (14.1%), follow-up visits were carried out as a teleconsultation. Few patients (5,7%) had no visits during the pandemic. Conclusions: The APOLON study confirms PZP effectiveness and safety in patients with mRCC in real-life setting. The efficacy of pazopanib remains significant in patients aged 65 years and older. It is highly associated with risk score. The COVID pandemics had limited impact on patients' cares.

Cabopoint: A phase II study of second-line cabozantinib in patients with metastatic renal cell carcinoma (RCC)

Background: Cabozantinib is an approved therapy for advanced RCC (in the USA) and in treatment-naive patients with intermediate/poor risk, as well as following VEGF-targeted therapy (in Europe). Trial design: Cabopoint (NCT03945773) is a phase II, open-label study of cabozantinib in adults with unresectable, locally advanced or metastatic clear-cell RCC, whose disease progressed after checkpoint inhibitor therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. A target of 250 patients at 50 European sites will receive cabozantinib (60 mg once daily;self-administered at home) for ≤ 18 months after the last patient receives their first dose. Safety assessments will occur every 2 weeks up to week 4, then every 4 weeks. Patients may continue cabozantinib after disease progression if there is clinical benefit. During follow-up, patients who discontinue early will be contacted every 12 weeks to assess survival and subsequent therapy. Each cohort will have an interim analysis when 60% of patients reach 12 months of follow-up. Cabopoint has been adjusted to allow the trial to continue during the COVID-19 outbreak, protecting participants in compliance with the study protocol.1 Alternative arrangements include: study drug dispensation to the participant's home if they cannot attend the study site;safety assessments at the study site or remotely at a local health care provider, within the protocol defined window;tumour assessments at a local radiology facility if they cannot attend the study site. Enrolment is permitted if the patient can be managed in compliance with the protocol and alternative arrangements.1 The limitations, risks and impact on data privacy of such arrangements will be accounted for and documented.

Impact of COVID-19 on ongoing oncological and hematological treatment strategy

Background: Outcomes and risk factors associated with COVID-19 worsening among cancer patients have previously been reported. However, the actual impact of SARs-Co-V2 infection on the cancer treatment strategy remains unknown. Here, we report the Gustave Roussy (GR) experience, one year after the onset of the pandemic focusing on the impact of COVID-19 in patients with ongoing management of oncohematological disease. Methods: All patients positively tested for SARS-CoV-2 and managed at GR between Mar 14th 2020 and Feb 15th 2021 (data cut-off) have been included. Patients underlying oncohematological disease and COVID19 characteristics have been collected. Cancer and COVID-19 management and outcomes have been assessed. Primary endpoint was the overall impact of COVID-19 on oncological and hematological treatment strategy assessed at 1, 3, 6 and 12 months. Results: At the time of the analysis, 423 patients (median age: 62 years) were found positive for SARS-CoV-2 and managed at GR with a median follow up of 5.6 months (0-13 months). Among them, 284 (67%) were admitted due to COVID-19. Clinical deterioration occurred in 87 patients (21%), 43 patients (10%) were transferred in intensive care unit and 123 (29%) patients died, among which 47 (11%) died from COVID-19. Overall, 329 (78%) patients were on active treatment for underlying oncohematological disease at time of COVID diagnosis. Impact of COVID-19 on cancer treatment strategy in those patients is presented in the Table. The majority (N=268, 81%) had no change in oncological strategy. For those who experienced a delay, median delay in treatment was 21 days (N=99, [1-77]), 30 days (N=15, [15-56]), 7 days (N=8,[3-35]) for systemic treatment, surgery and radiotherapy respectively. [Formula presented] Conclusions: COVID-19 outbreak is associated with a significant mortality in patients with cancer. However, for patients who did not die from COVID-19, we provide the first report supporting that ongoing treatment was maintained or could be resumed in the majority of cases in a timely manner. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Sustained cancer clinical trial activity during the COVID-19 pandemic

Background: The COVID-19 pandemic deeply threatens the rigorous conduct of clinical trials, notably by delaying site initiation visits, patient enrolment, treatment administration, trial-associated procedures, and data monitoring. Unlike most other medical specialties, clinical trials are an integral part of patient care in oncology. Limiting access to clinical trials therefore results in a loss of chance for patients. Methods: In this retrospective single-center study, we collected clinical trial-specific items (including patient-related or trial management-related items) during the first pandemic wave (March– June 2020) and lockdown (March 17th-May 11th) at Gustave Roussy, and compared them to those of the same period in 2019. Results: In March 2020, 84 phase I (P1) and 210 phase II/III (P2/3) trials were open. During the first pandemic wave, 21 (25%) P1 and 20 (9%) P2/3 trials were temporarily halted, following a unilateral sponsor decision in virtually all cases;all but one were industry-sponsored. Despite this, all important metrics of the P1/2 trial activity remained similar to those of 2019, including the number of patients referred for inclusion (599 vs 620), inclusion consultations (215 vs 247), patients starting treatment (130 vs 130), Internal Review Board (IRB) submissions (14 vs 16), and site initiation visits (11 vs 15), all in 2020 vs 2019, respectively. The impact of the first lock-down was more marked on P2/3, with 152 patient inclusions (vs 346 in 2019), 125 randomizations (vs 278), 43 IRB submissions (vs 50) and 34 site initiation visits (vs 40). However, in parallel, 475 patients were included in three “COVID and cancer” trials. Among the 443 P1 and 2851 P2/3 patients, 198 and 628 COVID-19 PCR were performed internally, and five and 15 (2.5%) were positive, respectively. One patient with a community-based COVID-19 died after transfer in intensive care. Conclusions: Cancer clinical trials can, and must be maintained despite challenges brought by COVID-19. Sharing experiences and retrospectively evaluating the impact on patients’ safety and cancer-related outcomes will be critical to durably improve the clinical trials conduct and to anticipate at best challenges brought by future similar crises. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Outcome of older cancer patientsinfected with Covid19 at Gustave Roussy Cancer Center

Background: The SARS-CoV-2 outbreak in Paris's region significantly affected Gustave Roussy Cancer Center.Previous analyses showed that mortality rate increases with age in the general population. Here, we report theGustave Roussy experience on older patients (OP) with cancer during the SARS-CoV-2 outbreak. Methods: Cancer pts with suspected SARS-CoV-2 infection were admitted at Gustave Roussy starting March 12th.Screening indications have been adapted over the time. All the COVID19 pts positively tested and managed atGustave Roussy between March 14th (1st positive case) and April 15th have been included in a REDCap database.Pts and underlying oncologic and COVID19 diseases characteristics have been collected. Cancer and COVID-19managements and outcomes have been assessed. The primary endpoint of this analysis was the clinicaldeterioration, defined as the need for O2 supplementation of 6l/min, or death of any cause. Results: Among the first 137 cancer pts diagnosed with SARS-CoV-2, 36 patients were aged 70 years (26%). Mostof them were female (61%) with a median age of 75.5 years old. Most frequent underlying cancers were solidtumors (92%) including GI (19%), lung (17%), GYN (14%), and head and neck (14%). Most OP (36%) were ECOGperformance status 2 versus 24% in younger patients (YP). The diagnosis of SARS-CoV-2 infection was made byRT-PCR or thoracic CT scan alone in 97% and 3% of the cases, respectively, in OP and in 92% and 8% in YP. MostOP experienced symptoms prior to testing (92%) compared to YP (80%). Symptoms differed according to age withmore cough with sputum production in OP (14% versus 5%), dyspnea (39% versus 31%), diarrhea (17% versus9%), shivers (8% versus 0%), sore throat (8% versus 4%), and no anosmia or agueusia. The majority of OP werehospitalized (81%) compared to 72% of YP and treated with HCQ/AZI (15;52%) with inclusion in the ONCOVID trial(EudraCT: 2020-01250-21) compared to 25 (35%) YP. They did not receive any IL-6 inhibitor. Only one OP wasadmitted in the ICU (3%). Clinical deterioration occurred in 10 OP (29%). There was no impact of age on clinicalworsening (HR=1.157;95%CI 0.55-2.42;p=0.7). However, age was associated with worse overall survival (OS)(HR=2.45 95%CI 1.02-5.92 ;p=0.0463). Results will be updated at the meeting. Conclusions: OP with cancer had a different disease presentation, same rate of clinical worsening, but worse OSin SARS-CoV-2 infection.

Outcome of older cancer patients infected with COVID-19 at Gustave Roussy Cancer Center

Background: The SARS-CoV-2 outbreak significantly affected Gustave Roussy cancer center. Here, we report the Gustave Roussy experience on older patients (OP) with cancer during the SARS-CoV-2 outbreak. Methods: Cancer pts with suspected SARS-CoV-2 infection were admitted at Gustave Roussy starting March, 12th. Screening indications have been adapted over time. All the COVID-19 pts positively tested and managed at Gustave Roussy between March 14th and April 15th have been included in a redcap database. Pts and underlying oncological and COVID-19 diseases characteristics have been collected. Cancer and COVID-19 managements, and outcomes have been assessed. The primary endpoint of this analysis was the clinical deterioration, defined as the need for O2 supplementation of 6l/min or more, or death of any cause. Results: Among the first 137 cancer pts diagnosed with SARS-CoV-2, 36 patients were aged 70 years old or over (26%). Most of them were female (61%) with a median age of 75.5 years old. Most frequent underlying cancers were solid tumors (92%) including GI (19%), lung (17%), GYN (14%) and head and neck (14%). Most OP (36%) were ECOG Performans status 2 versus 24% in younger patients (YP). The diagnosis of SARS-CoV-2 infection was made by RT-PCR or thoracic CT scan alone in 97% and 3% of the cases, respectively in OP and in 92% and 8% in YP. Most OP experienced symptoms prior to testing (92%) compared to YP (80%). Symptoms differed according to age with more cough with sputum production in OP (14% versus 5%), dyspnea (39% versus 31%), diarrhea (17% versus 9%), shivers (8% versus 0%), sore throat (8% versus 4%) and no anosmia nor agueusia. The majority of OP was hospitalized (81%) compared to 72% of YP and treated with HCQ/AZI (15;52%) compared to 25 (35%) YP with inclusion in the ONCOVID trial (EudraCT: 2020-01250-21). They did not receive any IL-6 inhibitor. Only one OP was admitted in the ICU (3%). Clinical deterioration occurred in 10 OP (29%). There was no impact of age on clinical worsening (HR=1.157;95%CI 0.55-2.42;p=0.7). However age was associated with worse overall survival (OS) (HR=2.45 95%CI 1.02-5.92;p=0.0463). Results will be updated at the meeting. Conclusions: OP with cancer had a different disease presentation, same rate of clinical worsening but worse OS in SARS-CoV-2 infection. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

CaboPoint: A phase II study of second-line cabozantinib in patients with metastatic renal cell carcinoma (RCC)

Background: Cabozantinib is an approved therapy for advanced RCC (in the USA) and in treatment-naïve patients with intermediate/poor risk, as well as following VEGF-targeted therapy (in Europe). Trial design: CaboPoint (NCT03945773) is a phase II, open-label study of cabozantinib in adults with unresectable, locally advanced or metastatic clear-cell RCC, whose disease progressed after checkpoint inhibitor therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. A target of 250 patients at 50 European sites will receive cabozantinib (60 mg once daily;self-administered at home) for ≤ 18 months after the last patient receives their first dose. Safety assessments will occur every 2 weeks up to week 4, then every 4 weeks. Patients may continue cabozantinib after disease progression if there is clinical benefit. During follow-up, patients who discontinue early will be contacted every 12 weeks to assess survival and subsequent therapy. Each cohort will have an interim analysis when 60% of patients reach 12 months of follow-up. CaboPoint has been adjusted to allow the trial to continue during the COVID-19 outbreak, protecting participants in compliance with the study protocol.1 Alternative arrangements include: study drug dispensation to the participant’s home if they cannot attend the study site;safety assessments at the study site or remotely at a local health care provider, within the protocol defined window;tumour assessments at a local radiology facility if they cannot attend the study site. Enrolment is permitted if the patient can be managed in compliance with the protocol and alternative arrangements.1 The limitations, risks and impact on data privacy of such arrangements will be accounted for and documented. Clinical trial identification: NCT03945773. Editorial acknowledgement: Dr Tamzin Gristwood of Oxford PharmaGenesis, Oxford, UK, provided medical writing and editorial support, which was sponsored by Ipsen, in accordance with Good Publication Practice guidelines. Legal entity responsible for the study: Ipsen. Funding: Ipsen. Disclosure: L. Albiges: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS;Advisory/Consultancy, Travel/Accommodation/Expenses: MSD;Advisory/Consultancy: Novartis;Advisory/Consultancy: Amgen;Advisory/Consultancy: Ipsen;Advisory/Consultancy: Roche;Advisory/Consultancy: Pfizer;Advisory/Consultancy: Merck;Advisory/Consultancy: AstraZeneca;Advisory/Consultancy: Exelixis;Advisory/Consultancy: Peloton Therapeutics;Advisory/Consultancy: Corvus Pharmaceuticals. M. Schmidinger: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer;Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche;Honoraria (self), Advisory/Consultancy: Novartis;Honoraria (self), Advisory/Consultancy: BMS;Honoraria (self), Advisory/Consultancy: MSD;Honoraria (self), Advisory/Consultancy: Merck;Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: EUSA;Honoraria (self), Advisory/Consultancy: Ipsen;Honoraria (self), Advisory/Consultancy: Exelixis;Honoraria (self), Advisory/Consultancy: EISAI;Honoraria (self), Advisory/Consultancy: Alkermes. N. Taguieva-Pioger: Full/Part-time employment: Ipsen. D. Perol: Honoraria (self): Roche;Honoraria (self): BMS;Honoraria (self): MSD;Honoraria (self): Ipsen;Honoraria (self): Pierre Fabre;Honoraria (self): Novartis;Honoraria (self): Takeda;Honoraria (self), Travel/Accommodation/Expenses: AstraZeneca;Research grant/Funding (institution): MSD Avenir. V. Gruenwald: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options: AstraZeneca;Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock opt ons: BMS;Honoraria (self), Research grant/Funding (institution), Shareholder/Stockholder/Stock options: MSD;Honoraria (self): Roche;Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Ipsen;Honoraria (self), Travel/Accommodation/Expenses: Bayer;Honoraria (self): Merck Serono;Honoraria (self): Janssen-Cilag;Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer;Honoraria (self): Lilly;Honoraria (self): PharmaMar;Honoraria (self), Research grant/Funding (institution): Novartis;Honoraria (self): EUSAPharm;Honoraria (self): Eisai.