Jason Harris

Patients with urothelial carcinoma who progress after treatment with platinum-containing chemotherapy may receive benefit with the combination systemic therapy regimen of cabozantinib (Cabometyx) and atezolizumab (Tecentriq), according to new data from the COSMIC-021 study (NCT03170960).

The trial is a multicenter phase 1b study evaluating the combination of cabozantinib with atezolizumab in various solid tumors. Sumanta K. Pal, MD, a clinical professor in the Department of Medical Oncology & Therapeutics Research and codirector of the Kidney Cancer Program at City of Hope in Duarte, California, presented results from urothelial carcinoma expansion cohort 2 (n = 30) in a poster presented as part of the 2020 American Society of Clinical Oncology Virtual Scientific Program.

At a median follow-up of 19.7 months, the objective response rate (ORR) was 27%, with 2 (6.7%) complete responses and 6 (20%) partial responses. The disease control rate was 63% and 16 (53%) patients had any reduction in target lesion size.

The median duration of response was not reached with the longest response ongoing at more than 15.6 months. The median time to response was 3.0 months (range, 1-6).

Investigators observed 22 progression-free survival events (PFS). The median PFS was 5.4 months (95% CI, 1.5-7.6).

These preliminary results do not suggest an association between PD-L1 expression and tumor response.

“A combination of cabozantinib and atezolizumab demonstrated encouraging clinical activity in patients with urothelial carcinoma previously treated with platinum-containing chemotherapy, with an objective response rate of 27% and deep and durable responses,” Pal said. “Additional cohorts evaluating the combination in urothelial carcinoma have been initiated in cisplatin-ineligible and cisplatin-eligible disease without prior systemic therapy, as well as urothelial carcinoma previously treated with checkpoint-inhibitor therapy.”

Ninety percent of diagnoses of urothelial carcinoma occur in patients aged 55 or older.

 It is the fourth most common cancer in men and accounts for 4.5% of all new cases of cancer in the U.S. each year.



COSMIC-021 is divided into 2 parts: a dose-escalation phase and an expansion-cohort phase.

Investigators in the dose-escalation phase determined the optimal dose of cabozantinib to be 40 mg daily when given in combination with 1200 mg atezolizumab every 3 weeks.

In the expansion-cohort phase, there are 24 cohorts across 12 tumor types: urothelial carcinoma, renal cell carcinoma, non–small cell lung cancer, metastatic castration-resistant prostate cancer (mCRPC), hepatocellular carcinoma, triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal cancer, head and neck cancer, and differentiated thyroid cancer.

To be eligible for the urothelial carcinoma cohort, patients had to be diagnosed with inoperable locally advanced, metastatic, or recurrent disease that had progressed on or after treatment with a platinum-containing chemotherapy. Patients were required to have an ECOC score of 0 or 1.

All patients in the cohort were included in the safety analysis. Twenty-seven (90%) patients experienced a treatment-related adverse event (TRAE). The most common were grade 1/2 asthenia (37%), diarrhea (27%), decreased appetite (23%), increased transaminases (23%), and mucosal inflammation (20%).

Seventeen (56.3%) patients experienced a grade 3/4 TRAE, the most common being grade 3 pulmonary embolism (13%) followed by grade 3 asthenia (6.7%). No other grade 3/4 TRAE occurred in more than 1 (3.3%) patient.

There was 1 incident of a grade 3 immune-related AE, chorioretinitis, and no incidences of grade 4 immune-related AEs.

Investigators did not observe any discontinuations due to TRAEs. “The combination exhibited an acceptable safety profile in this patient population,” Pal said.

Findings from the mCRPC cohort reported at the 2020 Genitourinary Cancers Symposium showed that the combination induced an ORR of 32%, including 2 complete responses and 12 partial responses. The ORR was 33% in subgroup of patients with high-risk clinical features, including visceral metastases and/or extra-pelvic lymph node metastases.

Pal SK, Agarwal N, Loriot Y, et al. Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study. J Clin Oncol. 38: 2020 (suppl; abstr 5013). doi:10.1200/JCO.2020.38.15_suppl.5013

American Cancer Society. Bladder Cancer Key Statistics. Accessed May 30, 2020. cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics

National Cancer Institute. SEER Stat Fact Sheets: Bladder Cancer. Accessed May 30, 2020. seer.cancer.gov/statfacts/html/urinb.html

American Cancer Society: Cancer Facts & Figures 2020. Accessed May 30, 2020. cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf

Exelixis announces encouraging results for cabozantinib in combination with atezolizumab in metastatic castration-resistant prostate cancer [news release]: Alameda, CA. Exelixis, Inc. Accessed May 30, 2020. bit.ly/39pNIcj

Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of cohort 6 of the COSMIC-021 Study. J Clin Oncol. 2020;38(suppl; abstr 139).

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Articles

Patients with urothelial carcinoma who progress after platinum-containing chemotherapy may receive benefit with the combination regimen of cabozantinib and atezolizumab, according to new data from the COSMIC-021 study.

Combination Therapy With Cabozantinib and Atezolizumab Gains Foothold in Urothelial Carcinoma

Patients with PD-L1-positive relapsed/refractory head and neck squamous cell carcinoma (HNSCC) who were treated in the KEYNOTE-048 trial experienced and improvement in progression-free survival after subsequent therapy (PFS2) with pembrolizumab (Keytruda) compared with the EXTREME regimen. The PFS2 benefit was consistent in patients who received pembrolizumab alone and those who received added chemotherapy.

In findings presented at the 2020 ASCO Virtual Scientific Meeting, lead author Kevin J. Harrington, MBBS, PhD, added that the combination of pembrolizumab plus chemotherapy also extended PFS2 for the total study population.

Among the total population, the 24-month PFS2 rate was 19.7% among those assigned to pembrolizumab (n = 301) compared with 11.4% in the EXTREME arm (n = 300). The median PFS2 was 9.0 months for both groups (HR, 0.90; 95% CI, 0.75-1.07).

For those in the total population assigned to pembrolizumab/chemotherapy (n = 281), the 24-month PFS2 rate was 21.4% versus 10.5% in favor of the experimental arm. Similarly, the median PFS2 was superior in the pembrolizumab/chemotherapy arm (n = 278) 10.3 vs 9.0 months; HR, 0.74; 95% CI, 0.62-0.88).

“Overall, these data support the use of pembrolizumab and pembrolizumab plus chemotherapy as first-line treatment of patients with relapsed and/or metastatic HNSCC,” he said.

In the phase 3 KEYNOTE-048 (NCT02358031), 882 patients with metastatic HNSCC were randomly assigned to pembrolizumab, pembrolizumab plus platinum-based chemotherapy and 5-fluorouracil (5-FU), or the EXTREME regimen consisting of cetuximab (Erbitux) plus platinum-based chemotherapy and 5-FU.

In this subsequent analysis, Harrington et al sought to evaluate outcomes for subsequent therapy in patients who progressed following first-line treatment. Eligible patients had never received systemic therapy for metastatic or recurrent disease and were considered incurable by local therapies. PFS2 was defined as time from randomization to objective tumor progression on next-line therapy or death from any cause.

Overall, investigators compared 301 patients assigned to pembrolizumab alone to 300 patients assigned to EXTREME. A total of 281 patients were assigned to pembrolizumab/chemotherapy versus 278 assigned to EXTREME.

Patients were assessed for PD-L1–positivity at a combined positive score (CPS) greater than or equal to 20 (³20) and CPS greater than or equal to 1 (³1).

Among patients with CPS ≥20, PFS2 at 24 months was 27.0% for pembrolizumab monotherapy (n = 133) compared with 12.5% for EXTREME (n = 122). The median PFS2 was 11.7 versus 9.4 months in favor of the pembrolizumab arm (HR, 0.64; 95% CI, 0.48-0.84).

For patients with CPS ≥20 assigned to pembrolizumab/chemotherapy, the 24-month PFS2 rate was 28.9% pembrolizumab combination (n = 126) compared with 12.0% for EXTREME n = 110). The median PFS2 was 11.3 versus 9.7 months in favor of the pembrolizumab arm (HR, 0.63; 95% CI, 0.47-0.84).

For patients with CPS ≥1 assigned to pembrolizumab monotherapy, the 24-month PFS2 rate was 22.0% pembrolizumab combination (n = 257) compared with 9.9% for EXTREME (n = 255). The median PFS2 was 9.4 versus 8.8 months in favor of the pembrolizumab arm (HR, 0.80; 95% CI, 0.66-0.96).

Among the CPS ≥1 population, the 24-month PFS2 rate assigned for those assigned to pembrolizumab/chemotherapy was 23.7% pembrolizumab combination (n = 242) compared with 9.0% for EXTREME (n = 235). The median PFS2 was 10.3 versus 8.9 months in favor of the pembrolizumab arm (HR, 0.66; 95% CI, 0.54-0.80).

Harrington concluded with an overview of the first subsequent therapies selected by investigators for their patients who developed progressive disease. Approximately half of all patients received any new cancer treatment in the total population of each arm: 49.5% in the pembrolizumab monotherapy arm, 40.9% in the pembrolizumab/chemotherapy arm, and 53.0% in the EXTREME arm. The largest number of patients received chemotherapy as their next line of treatment (44.9%, 31.3%, and 34.0%, respectively).

“As anticipated, patients who had not received the EXTREME regimen in the first line were more likely to receive EGFR inhibitor therapy, and conversely those who had not received an immune checkpoint inhibitor in the first line were more likely to receive [an immune checkpoint inhibitor] as their next treatment,” said Harrington.

Treatment with an EGFR inhibitor were 19.6%, 13.2%, and 6.3% for the pembrolizumab, pembrolizumab/chemotherapy, and EXTREME arms, respectively. Subsequent treatment with an immune checkpoint inhibitor were 2.0%, 4.3%, and 16.7%, respectively.

Based on previous data from KEYNOTE-048, the FDA approved pembrolizumab in June 2019 for the first-line treatment of patients with metastatic or unresectable recurrent HNSCC as monotherapy in patients with CPS ≥1 or in combination with platinum and FU irrespective of PD-L1 expression.

Single-agent pembrolizumab induced a 22% reduction in the risk of disease progression or death compared with the standard EXTREME regimen in patients with PD-L1–positive tumors (HR, 0.78; 95% CI, 0.64-0.96; 

 When combined with chemotherapy, the PD-1 inhibitor led to a 23% reduction in the risk of disease progression or death (HR, 0.77; 95% CI, 0.63-0.93; 

1. Harrington KJ, Rischin D, Greil R, et al. KEYNOTE-048: progression after the next line of therapy following pembrolizumab (P) or P plus chemotherapy (P+C) vs EXTREME (E) as first-line (1L) therapy for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 38:2020(suppl 15; abstr 6505). doi:10.1200/JCO.2020.38.15_suppl.6505

2. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. FDA. Accessed May 30, 2020. bit.ly/3djbOIf

Overall, these data support the use of pembrolizumab and pembrolizumab plus chemotherapy as first-line treatment of patients with relapsed and/or metastatic HNSCC.


Pembrolizumab Increases 24-Month PFS2 in PD-L1+ HNSCC

Performing surgery and radiation to stage IV breast tumors did not improve overall survival (OS) compared with systemic treatment alone, according to data from the ECOG-ACRIN E2108 trial presented ahead of the 2020 ASCO Virtual Scientific Program.

At a median follow-up of 59 months, investigators led by Seema A. Khan, MD, found no significant difference in OS between optimal systemic therapy plus locoregional therapy compared with optimal systemic therapy alone (68.4% vs 67.9%; HR, 1.09; 90% CI, 0.80-1.49; 

 = .63). The addition of locoregional therapy also failed to improve 3-year progression-free survival (

 = .40).

However, locoregional recurrence or progression was significantly higher in the systemic arm alone (25.6% vs 10.2%; 

 = .003).

“Based on the results of our study, women who present with a new diagnosis of breast cancer already in stage IV should not be offered surgery and radiation for the primary breast tumor with the expectation of a survival benefit,” Khan, the Bluhm Family Professor of Cancer Research and professor of surgery (breast surgery) at Northwestern University’s Feinberg School of Medicine, said in a news release.

 “When making these decisions, it is important to focus energy and resources on proven therapies that can prolong life.”

Traditionally, physicians have believed local therapy would not provide any additional survival benefit beyond systemic treatment could offer once metastases had occurred. Some studies suggested that surgery to remove the tumor would be beneficial, but these findings were criticized because women receiving surgery tended to be younger, healthier, and have less severe disease.

Investigators in the phase 3 ECOG-ACRIN E2108 trial (NCT01242800) recruited 390 women from February 2011 through July 2015 to determine whether the addition of locoregional treatment improved OS. Overall, 256 eligible patients were assigned to systemic therapy based on patient and tumor characteristics. Those who did not progress during 4 to 8 months of treatment were then assigned to continue systemic therapy alone (n = 131) or plus locoregional treatment with surgery and radiation for the intact primary tumor (n = 125).

Khan said these data are similar to findings from a study of 716 women with de-novo metastatic breast cancer treated at Tata Memorial Centre from February 2005 to January 2013 (NCT00193778). A total of 173 women were assigned to locoregional treatment while 177 received only systemic treatment.



At a median follow-up of 23 months, the median OS was 19.2 months (95% CI, 15.98-22.46) in the locoregional treatment group compared with 20.5 months (95% CI, 16.96-23.98) in the systemic treatment group (HR, 1.04; 95% CI, 0.81-1.34; 

 = .79). Two-year OS also showed no advantage for locoregional treatment (41.9% vs 43.0%).

“When combined with the results of an earlier trial in Mumbai, India, these results tip the scales against the possibility that local therapy to the breast tumor will help women live longer,” Khan said. “The Indian trial had a similar design to E2108, and also showed similar results between the 2 treatment groups.”

Investigators in ECOG-ACRIN E2108 evaluated health-related quality of life using the FACT-B Trial Outcome Index, which measures factors such as depression, anxiety, and well-being. Results showed that no quality-of-life advantage was associated with locoregional therapy.

“This result was a little surprising since one of the reasons for considering surgery and radiation is the idea that growth of the tumor will impair quality of life,” Khan said. “Instead, we find that the adverse effects of surgery and radiation appear to balance out the gains in quality of life that were achieved with better control of the primary tumor.”

1. Khan SA, Zhao F, Solin LJ, et al. A randomized phase III trial of systemic therapy plus early local therapy versus systemic therapy alone in women with de novo stage IV breast cancer: a trial of the ECOG-ACRIN Research Group (E2108). 

. 2020;38(suppl; abstr LBA2). doi:10.1200/JCO.2020.38.18_suppl.LBA2

2. ECOG-ACRIN Cancer Research Group. Surgery and radiation do not extend survival in newly diagnosed metastatic breast cancer. Published May 28, 2020. https://bit.ly/3ddC2M3. Accessed May 28, 2020.

3. Badwe R, Hawaldar R, Nair N, et al. Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial. 

. 2015;16(13):1380‐1388. doi:10.1016/S1470-2045(15)00135-7

"Based on the results of our study, women who present with a new diagnosis of breast cancer already in stage IV should not be offered surgery and radiation for the primary breast tumor with the expectation of a survival benefit."

Overall Survival Not Increased With Locoregional Therapy in Advanced Breast Cancer

Death in patients with progressive cancer within 30 days of the coronavirus disease 2019 (COVID-19) diagnosis was 5.2 times compared with patients in remission or with no evidence of disease, data from the COVID-19 and Cancer Consortium (CCC19) registry shows.

The risk for death was 1.79 times greater for those with stable cancer compared with patients who had no evidence of disease.

Lead author Jeremy L. Warner, MD, and his colleagues assessed data on 928 patients for 30-day all-cause mortality. At a median follow-up of 21 days, 121 (13%) patients in the study had died of COVID-19. "That's about twice what the [death rate] is for all patients across the globe, which is about 6.5%," he said.

As of May 28, the World Health Organization had recorded more than 5.5 million cases of COVID-19 and more than 351,000 deaths.

 According to the Centers for Disease Control and Prevention, 12% of US deaths for the week ending May 16 were attributed to pneumonia, influenza, or COVID-19.



Warner, associate professor of medicine and biomedical informatics at Vanderbilt University Medical Center in Nashville, Tennessee, presented the results during a press briefing in advance of the 2020 ASCO Virtual Scientific Program. The data were also published in 

.

Warner said that treating COVID-19 with a combination of hydroxychloroquine and azithromycin, a regimen that has been promoted by President Donald Trump, was associated with a 2.89-fold greater risk of 30-day mortality compared with patients who did not receive either drug.

"I will add that this final result is of uncertain validity due to a high risk of residual confounding," Warner added. "For example, patients receiving this combination were more likely to have severe disease or more likely to be hospitalized."

Patients who later died after receiving hydroxychloroquine and azithromycin were more likely to have had slightly diminished daily physical function, received cancer therapy less than 2 weeks before COVID-19 diagnosis, have Rh-positive blood type, be of non-Hispanic ethnicity, and use statins at baseline.

Investigators did not observe an increased risk for death associated with the use of either drug as monotherapy.

On May 22, 

 published results online from an observational study of 96,032 patients hospitalized with COVID-19 at 671 hospitals worldwide. Mehra et al found that hydroxychloroquine was associated with an increased risk for in-hospital mortality (18.0%; HR, 1.335; 95% CI, 1.223-1.457) and de-novo ventricular arrhythmia during hospitalization (6.1%; HR, 2.369; 95% CI, 1.935-2.900) compared with patients who did not receive the antimalaria drug.



CCC19 includes 108 organizations in 43 states that collect and share data about patients with cancer who have been diagnosed with COVID-19. The consortium aims to collect and disseminate prospective, granular, uniformly organized information on these patients as broadly and as rapidly as possible.

Overall, 43% of patients included in the study had active cancer, 39% were on active cancer treatment, and 45% were in remission. The most common cancer was breast (21%), followed by prostate (16%), gastrointestinal (12%), lymphoma (11%), and thoracic (10%).

Half of patients in the registry were men and half were white. African Americans and Hispanics each made up 16% of the cohort, with other races and ethnicities making up 15%. The median age was 66 years and 30% of patients were aged 75 years or older.

More than half (52%) of patients were never smokers, 37% were former smokers, 5% were current smokers. Sixty-eight percent had ECOG status of 0 or 1 and 13% had an ECOG status of 2 or higher. ECOG status was unknown for 19% of patients.

ECOG status of 2 or higher (35%), active cancer (25%), age older than 75 (25%), former smoker (20%), and male sex (17%), were all independent risk factors for COVID-19 mortality. Compared with patients with an ECOG score of 1 or lower, those with a score of 2 or higher had a 3.89 times greater risk for 30-day mortality. The risk for 30-day mortality was 1.6 times greater for smokers compared with nonsmokers and 1.63 times greater for men compared with women. Each additional decade of life was associated with a 1.83-fold increased risk for death.

"The only characteristic we found that was associated with a lower rate of mortality was not having comorbidities, although the number of deaths in that group was small and does not reach statistical significance," Warner added. Three (2%) patients in that subgroup died during the study.

Investigators did not find any statistically significant rates of death based on race or ethnicity.

"The cancer care community urgently needs data on the effects of COVID-19, specifically in patients with cancer," ASCO President Howard A. Burris III, MD, stated in a news release. "How we improve the care we provide these patients and reduce the number of deaths and severe consequences associated with this disease are among the top questions. The COVID-19 and Cancer Consortium registry is a great example of the community quickly coming together to identify and collect the data we need on a large scale."

1. Warner JL, Rubinstein S, Grivas P, et al. Clinical impact of COVID-19 on patients with cancer: Data from the COVID-19 and Cancer Consortium (CCC19). 2020 ASCO Virtual Scientific Program. Abstract LBA110.

2. Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Accessed May 28, 2020. doi:10.1016/S0140-6736(20)31187-9

3. World Health Organization. Coronavirus disease (COVID-19) dashboard. Accessed May 28, 2020. 

4. Centers for Disease Control and Prevention. COVIDView. Accessed May 28, 2020. 

https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html

5. Mehra MR, Desai SS, Ruschitzka F, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Accessed May 28, 2020. doi:10.1016/S0140-6736(20)31180-6

The risk for death from COVID-19 was greater for patients with stable cancer compared with patients who had no evidence of disease.

Author | Jason Harris

Articles

Combination Therapy With Cabozantinib and Atezolizumab Gains Foothold in Urothelial Carcinoma

Pembrolizumab Increases 24-Month PFS2 in PD-L1+ HNSCC

Overall Survival Not Increased With Locoregional Therapy in Advanced Breast Cancer

COVID-19 Mortality Shows Strong Correlation With Active Cancer