Phase 2 study of neoadjuvant cabozantinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma

Background: Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met, AXL and VEGFR2 that has been shown to reduce tumor growth, metastasis, and angiogenesis. After the promising results from the METEOR, CABOSUN and Checkmate-9ER trials, cabozantinib was approved for use in patients with advanced renal cell carcinoma (RCC). The increased response rates with cabozantinib in metastatic RCC, along with the other neoadjuvant TKI data, support an expanded role for cabozantinib in the neoadjuvant setting. Methods: Patients with clinical stage ≥ T3Nx or TanyN+ or deemed unresectable by the surgeon with biopsy-proven clear cell RCC were eligible for this study, and received cabozantinib at a starting dose of 60 mg daily for 12 weeks. The primary outcome was objective response rate per RECIST v1.1 (complete and partial responses) at week 12 after the administration of cabozantinib as determined by independent radiologist review. Secondary outcomes included safety, tolerability, clinical outcome (DFS, OS), surgical outcome and quality of life. Results: As of 20 September 2021, 16 biopsy-proven clear cell RCC patients were treated with neoadjuvant cabozantinib. The median age was 56 years (range: 41-84 years) and 81.2% male. All patients completed 12 weeks of treatment, and 15 of them underwent surgery as planned without any delay after completion of 4 weeks wash-out. One patient refused to undergo surgery due to personal reasons and received further systemic treatment. Five patients (31.2%) experienced a partial response, and 11 patients had stable disease. There was no progression of disease while on cabozantinib. Median reduction of primary renal tumor size was 24% (range: 6-45%). The one patient who was deemed to be unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common AEs were diarrhea, nausea, fatigue, hypertension, anorexia, and palmar-plantar erythrodysesthesia syndrome. Intraoperatively, we did not experience any immediate complications. Postoperatively, no surgical complications related to the drug were noted. No treatment related grade 4 or 5 AEs related to cabozantinib or surgery occurred. Two patients had died at the time of analysis (1 due to COVID and 1 unknown cause). Conclusions: Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC. Additional data will be reported including long term outcomes, correlative studies, quality of life, and frailty/sarcopenia indices.

Racial and ethnic disparities among patients with breast cancer and COVID-19

Background: Racial/ethnic minorities have disproportionately increased risk of contracting COVID-19 and experiencing severe illness;they also have worse breast cancer (BC) outcomes. COVID-19 outcomes among racial/ethnic minorities with BC are currently unknown. We sought to compare clinicopathologic characteristics and COVID-19 outcomes stratified by race/ethnicity. Methods: The COVID-19 and Cancer Consortium registry (NCT04354701) was used to identify patients with invasive BC and laboratory-confirmed SARS-CoV-2 diagnosed in the U.S. between 2020-03-06 and 2021-02-04. The primary analysis was restricted to women who selfidentified as non-Hispanic White (NHW), nonHispanic Black (NHB), or Hispanic (H). Demographic, cancer characteristics, and COVID-19 outcomes were evaluated. COVID-19 outcomes included: hospital admission, intensive care unit (ICU) admission, mechanical ventilation, death within 30 days of COVID-19 diagnosis and death from any cause during follow-up. Descriptive statistics were used to compare clinicopathologic characteristics and Fisher exact tests were used to compare COVID19 outcomes across the 3 racial/ethnic groups. Results: A total of 1133 patients were identified of which 1111 (98%) were women;of which 575 (52%) NHW, 243 (22%) NHB, 183 (16%) H, and 110 (10%) other/unknown. Baseline characteristics differed among racial/ethnic groups. H were younger (median age: NHW 63y;NHB 62y;H 54y) and more likely to be never smokers (NHW 62%;NHB 62%;H 78%). NHB had higher rates of obesity (NHW 40%;NHB 54%;H 46%), diabetes (NHW 16 %;NHB 32%;H 20%) and combined moderate and severe baseline COVID-19 at presentation (NHW 28%;NHB 42%;H 28%). Cancer characteristics are as shown (Table). Significant differences were observed in outcomes across racial/ethnic groups including higher rates of hospital admission (NHW 34%;NHB 49%;H 34%;P <0.001), mechanical ventilation (NHW 3%;NHB 9%;H 5%;P=0.002), 30-day mortality (NHW 6%;NHB 9%;H 4%;P=0.043) and total mortality (NHW 8%;NHB 12%;H 5%;P=0.05) among NHB compared to NHW and H. Conclusions: This is the largest study to show significant differences in COVID-19 outcomes by racial/ethnic groups of women with BC. The adverse outcomes in NHB could be due to higher moderate to severe COVID-19 at presentation and preexisting comorbidities. H did not have worse outcomes despite having more active disease and recent anti-cancer therapy, including with cytotoxic chemotherapy - potentially due to younger age and nonsmoking status. (Table Presented).

Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

Clinical impact of COVID-19 on patients with cancer: Data from the COVID-19 and Cancer Consortium (CCC19)

Background: There are limited data on COVID-19 in patients with cancer. We characterize the outcomes of patients with cancer and COVID-19 and identify potential prognostic factors. Methods: The COVID- 19 and Cancer Consortium (CCC19) cohort study includes patients with active or prior hematologic or invasive solid malignancies reported across academic and community sites. Results: We included 1,018 cases accrued March-April 2020. Median age was 66 years (range, 18-90). Breast (20%) and prostate (16%) cancers were most prevalent;43% of patients were on active anti-cancer treatment. At time of data analysis, 106 patients (10.4%) have died and 26% met the composite outcome of death, severe illness requiring hospitalization, and/or mechanical ventilation. In multivariable logistic regression analysis, independent factors associated with increased 30- day mortality were age, male sex, former smoking, ECOG performance status (2 versus 0/1: partially adjusted odds ratio (pAOR) 2.74, 95% CI 1.31-5.7;3/4 versus 0/1: pAOR 5.34, 95% CI 2.44-11.69), active malignancy (stable/responding, pAOR 1.93, 95% CI 1.06-3.5;progressing, pAOR 3.79, 95% CI 1.78-8.08), and receipt of azithromycin and hydroxychloroquine. Tumor type, race/ethnicity, obesity, number of comorbidities, recent surgery, and type of active cancer therapy were not significant factors for mortality. Conclusions: All-cause 30-day mortality and severe illness in this cohort were significantly higher than previously reported for the general population and were associated with general risk factors as well as those unique to patients with cancer. Cancer type and treatment were not independently associated with increased 30-day mortality. Longer follow-up is needed to better understand the impact of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.