Kristie L. Kahl

Treatment with cabozantinib (Cabometyx) in combination with atezolizumab (Tecentriq) demonstrated promising clinical activity in patients with advanced clear cell renal cell carcinoma (ccRCC), according to results from the phase 1b COSMIC-021 study presented at the virtual 2020 ESMO Congress.

Objective response rates (ORRs) per investigator by RECIST v1.1 were 53% (80% CI, 41-65) in the 40-mg cohort and 58% (80% CI, 46-70) in the 60-mg cohort. Complete responses were observed in 1 patient in the 40-mg group and 4 patients in the 60-mg group; while 17 partial responses in each cohort were also seen. Fourteen patients in the 40-mg group and 12 patients in the 60-mg group experienced stable disease. Moreover, only 2 patients in each group had progressive disease.

“The combination of cabozantinib and atezolizumab demonstrated encouraging clinical activity in previously untreated patients with advanced ccRCC,” Sumanta Kumar Pal, MD, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, said during a presentation of the ccRCC cohort at the virtual Congress.

In the trial, the initial cohort of patients received 40 mg of cabozantinib, while an expansion cohort was administered 60 mg. Median follow-up for the 40- and 60-mg dose groups were 25.8 months and (range, 20-33) and 15.3 months (range, 10-32), respectively.

The 40-mg group demonstrated a disease control rate (DCR) of 94%, while the 60-mg group showed a DCR of 92%. Duration of response has not been reached in the 40-mg cohort (12.4 months to not evaluable), while the 60-mg group’s DOR was 15.4 months (8.1 to not evaluable).

The time to objective response in the 40- and 60-mg groups were 1.4 months (range, 1-19) and 1.5 months (range, 1-7), respectively.

Cabozantinib administered at 40 mg induced a median progression-free survival (PFS) of 19.5 months (95% CI, 11.0 to not reached), while the 60-mg dose showed a median PFS of 15.1 months (95% CI, 8.2-22.3).

Any reduction in tumor target lesions occurred in 94% of the 40-mg cohort and 92% of the 60-mg group. “Many patients with sarcomatoid features had a large target reduction,” Pal added.

The investigators also evaluated baseline tumor PD-L1 and CD8 T-cell status to determine lesion change and response. They found that baseline PD-L1-positive status and CD8-positive T cells were associated with greater tumor lesion reductions and with overall response (

 = .0003). In addition, T cell Rich tumors (CD68high and CD8high) were associated with greater tumor shrinkage from baseline and higher overall response, with 10 of 13 patients who responded to treatment with cabozantinib (77%). “The status of the pretreatment tumor with respect to the immune cell population may contribute to tumor susceptibility to study treatment and warrants further investigation,” Pal said.

At data cutoff, 14 and 18 patients, respectively, in the 40- and 60-mg cohorts remained on treatment with cabozantinib in combination with atezolizumab.

In total 19 adverse events (AEs; 56%) in the 40-mg group and 31 (86%) in the 60-mg group led to cabozatinib dose reductions. Seven (21%) and 11 (31%) patients, respectively, discontinued treatment due to radiographic progression. In addition, 8 (24%) and 7 (19%) patients discontinued treatment due to treatment-related AEs (TRAEs) from cabozatinib and/or atezolizumab.

Almost all patients experienced TRAEs, which included diarrhea, fatigue, nausea, dysgeusia, hypertension, increased ALT, palmar-plantar erythrodysesthesia, stomatitis, increased AST, hypophosphatemia, decreased appetite, pruritus, hypothyroidism, decreased weight, increase lipase, mucosal inflammation, and proteinuria.

“Cabozantinib inhibits tyrosine kinases, including MET, VEGF receptors, and TAM family of kinases,” Pal explained. “It promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors.”

The agent has shown promising activity in combination with immune checkpoint inhibitors in tumor types including renal cell carcinoma, urothelial carcinoma, prostate cancer, lung cancer, and hepatocellular carcinoma.

The phase 1b COSMIC-021 study was designed to evaluate cabozantinib in combination with atezolizumab in patients with solid tumors.

To be eligible for the study, patients must have been diagnosed with advanced or metastatic ccRCC, had no prior systemic therapy for RCC, had measurable disease per RECIST v1.1, and had an ECOG performance score of 0 or 1.

The initial cohort of patients in the trial received 40 mg of cabozantinib oral once daily and 1200 mg of atezolizumab intravenously (IV) every 3 weeks (n = 34). Subsequently, in the expansion cohort, additional patients received 60 mg of cabozantinib oral once daily with the same atezolizumab regimen (n = 36) to evaluate the safety and efficacy of the higher dose.

ORR by the investigator per RECIST v1.1 served as the primary end point of the expansion phase of the study. Safety served as the secondary end point, while exploratory end points included PFS and correlations of biomarkers with outcomes.

Ten patients with ccRCC (4 at the dose level of 40 mg and 6 at the dose level of 60 mg) were included in the presentation at the virtual Congress. Data were presented for all 70 patients with ccRCC at the data cutoff of July 21, 2020.

Median age was 68 years (range, 39-87) in the 40-mg dose group and 60 years (range, 42-82) in the 60-mg dose group. In both groups, the majority of patients were male (79% vs 72%, respectively), and had an ECOG score of 0 (79% vs 69%), intermediate IMDC risk (76% vs 58%), prior nephrectomy (85% vs 89%), and metastases in the lung (79% vs 75%).

The investigators are now conducting the phase 3 CONTACT-03 trial (NCT04338269), designed to evaluate cabozantinib, with or without atezolizumab, in patients with RCC who were previously treated with an immune checkpoint inhibitor.

1. Pal S, Tsao CK, Suarez C, et al. Cabozantinib (C) in combination with atezolizumab (A) as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from the COSMIC-021 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 702O.

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“The combination of cabozantinib and atezolizumab demonstrated encouraging clinical activity in previously untreated patients with advanced ccRCC,” said investigator Sumanta Kumar Pal, MD.

Cabozantinib combo induces clinical activity in advanced ccRCC

A novel BiTE immuno-oncology therapy, AMG 160, demonstrated a manageable safety profile, with preliminary evidence of efficacy in men with metastatic castration-resistant prostate cancer (mCRPC) who were heavily pretreated, according to preliminary results from a phase 1 study (NCT03792841) presented at the virtual 2020 ESMO Congress.

“Despite the long list of agents now approved for the treatment of metastatic castration-resistant prostate cancer, there remains an urgent need for treatments that can overcome resistance to hormonal therapies, chemotherapies, and radiation therapies. And despite impressive activity in other cancers, novel immune-based therapies have offered limited efficacy in mCRPC,” Ben Tran, MBBS, FRACP, Peter MacCallum Cancer Centre, Melbourne, Australia, explained during a presentation at the virtual Congress.

Therefore, he and his colleagues evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of AMG 160—a targeted half-life extended BiTE (bispecific T-cell engager) immune therapy that engages patients’ own T cells to kill prostate cancer cells by binding CD3 on T cells and prostate-specific membrane antigen (PSMA) on cancer cells.

In the global, open-label phase 1 study, the investigators will evaluate the safety and tolerability of AMG 160 monotherapy (part 1) or in combination with pembrolizumab (Keytruda; part 2) in men with mCRPC that is refractory to prior novel hormonal therapy and 1 to 2 taxane regimens and evidence of progressive disease.

“The study is nearing completion of the dose exploration phase 1b, followed by those expansion phase armory objectives to evaluate the safety and tolerability of AMG 160 and to determine its recommended phase 2 dose and secondary objectives to characterize pharmacokinetics and evaluate preliminary anti-tumor activity,” Tran said.

AMG 160 was administered as a short IV infusion every 2 weeks at doses of 0.003 mg to 0.9 mg.

Patients were a median age of 66 years (range, 49-78). The majority of patients were white (79.1%) and had 4 or more prior lines of therapy (60.5%). Median PSA at baseline was 79.2 μg/L (range, 0.1-4035.0 μg/L).

Forty-three patients received ≥ 1 dose of AMG 160 monotherapy, of which 41 (95.3%) experienced treatment-emergent adverse events (TEAEs). In addition, 19 patients remained on treatment at the time of data analysis.

Forty-one patients experienced treatment-related AEs (TRAEs), including cytokine release syndrome (CRS; 90.7%), fatigue (44.2%), vomiting (44.2%), nausea (39.5%), pyrexia (37.2%), headache (34.9%), diarrhea (32.6%), dry mouth (30.2%), rash (27.9%), hypophosphatemia (25.6%), hypotension (23.3%), chills (23.3%), dysgeusia (23.3%), and decreased appetite (20.9%). Of note, no grade 5 events occurred and none resulted in treatment discontinuation. In total, 3 reversible dose-limiting toxicities occurred (grade 3 rash, n = 2; grade 3 gastrointestinal hemorrhage, n = 1).

CRS observed in patients was reversible and manageable. The AE was most severe in cycle 1 and was associated with fever, hypotension, transient transaminitis, nausea/vomiting, and/or diarrhea. There were no grade 4/5 CRS events or treatment discontinuations. Grade 2 CRS occurred in 26 patients (60.5%) and grade 3 in 11 patients (25.6%).

Of the 30 patients assessed for antidrug antibodies (ADAs), 6 (20.0%) had ADAs affecting drug exposure between cycles 1 and 10; however, no AEs associated with ADAs occurred.

“A number of mitigation strategies were used to improve the CRS profile of AMG 160,” Tran said. “Prophylactic mitigation was step dosing or dose priming, in which lower running doses were given prior to the maintenance target dose, which is administered every 2 weeks. Free medication with dexamethasone and prophylactic hydration with IV normal saline were also administered. These mitigation strategies appear to be effective in minimizing the risk of grade 3 serious events and serious adverse events.”

In total, 27.6% of patients had a confirmed PSA response to AMG 160. Overall, 68.6% of patients showed any PSA decline across all monotherapy dose cohorts and 34.3% of patients showed ≥ PSA50 reduction.

Among the 15 patients with measurable disease, 3 patients experienced a partial response (2 confirmed) and 8 patients had stable disease. Moreover, 44.2% of patients remained on AMG 160 at the time of data analysis, with 6 (14.0%) patients continuing treatment for ≥ 6 months.

Maximum tolerated dose has not been reached and dosing optimization of AMG 160 continues. Meanwhile, the investigation of AMG 160 in combination with pembrolizumab is in progress.

B. Tran, L. Horvath, T. Dorff, et al. Results from a phase I study of AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 609O.

Treatment with AMG 160 showed a manageable safety profile with preliminary efficacy in patients with metastatic castration-resistant prostate cancer.

Novel BiTE immuno-oncology therapy appears safe with preliminary efficacy in mCRPC

Olaparib (Lynparza) significantly prolonged overall survival (OS), compared with enzalutamide (Xtandi) or abiraterone (Zytiga) plus prednisone, in men with metastatic castration-resistant prostate cancer who had tumors with at least 1 alteration in 

 and whose disease had progressed during previous treatment with a next-generation hormonal agent.

In particular, the risk of death was 31% lower with olaparib than with control therapy, despite substantial crossover from control therapy to olaparib.

Updated fndings from the randomized, open-label phase 3 PROfound trial (NCT02987543) were presented at the 2020 ESMO Virtual Congress and were simultaneously published in the 

“Exploratory analysis suggests that patients with BRCA mutations achieve the most benefit and additional studies may be required to further delineate genomic indicators of PARP response, particularly for those with less common gene alterations,” Joaquin Mateo, MD, Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona, Spain, said during a presentation of the updated OS findings at the Congress.

“PROfound is the first randomized trial to prospectively demonstrate overall survival improvement in a molecularly-defined subset of prostate cancer, supporting implementation of genomic testing in daily clinical practice,” he added.

Median OS was superior with olaparib, compared with control therapy in cohort A (19.1 months vs 14.7 months; HR, 0.69; 95% CI, 0.50-0.97; 

 = .02) and cohort B (14.1 months vs 11.5 months; HR, 0.96; 95% CI, 0.63-1.49).

The crossover-adjusted analysis included 86 of 131 patients (66%) in the control group who had crossed over to receive olaparib, including 56 (67%) in cohort A. Patients were eligible for crossover if they had radiographic disease progression, no other subsequent anticancer therapy, any toxicities from prior therapy grade £ 1, and agreed to continue with the study visit schedule.

A sensitivity analysis that adjusted for crossover to olaparib showed a hazard ratio for death of 0.42 (95% CI, 0.19-0.91) in cohort A, and 0.83 (95% CI, 0.11-5.98) in cohort B. Moreover, the analysis showed a hazard ratio of 0.55 (95% CI, 0.29-1.06) in the overall population in the study.

Median duration of treatment with olaparib in patients who crossed over was 4.8 months, and median duration of treatment with control therapy was 3.9 months. The researchers noted that this was an investigator-assessed end point, which could mean the results are potentially subject to reporting bias. “Patients who crossed over from control therapy to receive olaparib had a shorter median duration of olaparib exposure (4.8 months) than those who were randomly assigned to receive olaparib (7.6 months). Thus, earlier treatment with olaparib may have an advantage over its use later in the disease course,” they wrote.

The safety profile of olaparib appeared consistent with that found in the primary analysis. No cumulative toxic effects were observed during the extended exposure period.

The most common adverse events among the patients in the olaparib group and those who crossed over to receive olaparib were anemia (39%), nausea (36%), and fatigue or asthenia (32%). Treatment with olaparib was discontinued because of anemia in 7% of patients and because of neutropenia, thrombocytopenia, nausea, vomiting, or fatigue or asthenia in 1% of the patients for each.

The PROfound trial enrolled patients with metastatic castration-resistant prostate cancer who had alterations in at least 1 of 15 prespecified genes with a direct or indirect role in homologous recombination repair (HRR) and whose disease had progressed during previous treatment with a next- generation hormonal agents.

Cohort A (n = 245) consisted of patients with at least 1 alteration in 

, while cohort B (n = 142) comprised patients with at least one alteration in any of the other 12 prespecified genes.

Patients were randomly assigned 2:1 to receive either olaparib or the physician’s choice of enzalutamide or abiraterone. In cohort A, 162 patients received 300 mg olaparib twice daily and 83 patients were assigned to control therapy. In cohort B, 94 patients received the same olarparib regimen while 48 patients were in the control arm.

The primary end point was imaging-based progression-free survival (PFS) in cohort A, according to blinded independent central review.

In cohort A, imaging-based PFS was significantly longer in the olaparib arm, compared with the control arm (median, 7.4 months vs. 3.6 months; HR, 0.34; 95% CI, 0.25-0.47; 

 < .001). In the initial analysis, a significant benefit was also observed with confirmed objective response rate and the time to pain progression.

“PROfound is the first positive phase 3 PARP inhibitor trial in metastatic castration-resistant prostate cancer, meeting its primary end point of prolonged radiographic progression-free survival for metastatic castration-resistant prostate cancer with alterations in 

progressing on prior next-generation hormonal agents and treated with olaparib versus with enzalutamide or abiraterone,” Mateo said, adding that these data supported the FDA’s approval of olaparib in this setting.

1. J.S. de Bono, J. Mateo, K. Fizazi, et al. Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 610O.

2. M. Hussain, J. Mateo, K. Fizazi, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. 

3. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. 

The PARP inhibitor reduced the risk for death by 31% in men with metastatic castration-resistant prostate cancer, compared with enzalutamide or abiraterone plus prednisone.

Olaparib significantly improves OS in mCRPC subgroup

From 1999 to 2016, testosterone levels have declined in adolescent and young adult men (AYA), according to results presented at the 2020 American Urological Association Virtual Experience

“Overall male testosterone decline can be attributed to multiple etiologies. The United States has an aging population with older males exhibiting lower testosterone levels. Furthermore, overall population has an increase in comorbidities, including diabetes, which may have cause this testosterone decrease nationally,” Soum Lokeshwar, MD, MBA, incoming urology resident at Yale School of Medicine, New Haven, Connecticut, said during a press briefing.

“However, most of these explanations for testosterone deficiency may be attributed to age. This time-dependent decline in testosterone has not been investigated in adolescent and young adult males,” added Lokeshwar, who was at the University Of Miami Miller School of Medicine, Miami, Florida, at the time of the study.

Testosterone deficiency has a prevalence of 10%-40% among adult males, and 20% among AYA men aged 15-39 years, he added. Therefore, Lokeshwar and colleagues hypothesized that serum total testosterone levels will decline in AYA men.

The investigators used data from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2016 to analyze serum testosterone level changes over time in 4045 AYA males. During the study periods, 3 different assays (Biotin-Streptavidin from 1999-2004, IS-Liquid Chromatography from 2011-2012, and High-Performance-Liquid-Chromatography Tandem Mass Spectrometry from 2013 onwards) were used. However, of note, they demonstrate comparable testosterone values with only some additional accuracy in the latest modality, Lokeshwar said.

After controlling for confounders—including year of study, age, race, BMI, comorbidity status, alcohol and smoking use, and level of physical activity—total testosterone was lower among men in the later (2011-2016) versus earlier (1999-2000) cycles (

 < 0.001). Mean total testosterone decreased from 1999-2000 (605.39 ng/dL), 2003-2004 (567.44 ng/dL), 2011-2012 (424.96 ng/dL), 2013-2014 (431.76 ng/dL), and 2015-2016 (451.22 ng/dL; all 

Elevated BMI was associated with reduced total testosterone levels (P < .0001), with the mean BMI increasing from 25.83 in 1999-2000, to 27.96 in 2015-2016 (

 = 0.0006). Lokeshwar noted that even men with a normal BMI (18.5-24.9) had declining total testosterone levels (

Potential causes include increased obesity/BMI, assay variations

According to Lokeshwar, potential causes for these declines could be increased obesity/BMI, assay variations, diet/phytoestrogens, declined exercise and physical activity, fat percentage, marijuana use, and environmental toxins.

“We’ve seen that lower values of testosterone have been associated with increased comorbidities and an increase risk for all-cause mortality. This decline specifically, in these young adult men, with increased obesity may lead to an increase in precocious cancer,” Lokeshwar said, adding such decreases can also result in a lower libido and an increased risk for erectile dysfunction.

“This is especially worrisome in this young adult age group, as many men feel stigma and are less likely to seek care for these low libido and erectile dysfunction.” Lokeshwar added. “Testosterone levels in AYA men are used as the benchmark normal levels for testosterone. This is very scary, because generally, when we think of normal values of testosterone, we treat based upon this age group. This may ultimately lead to the undertreatment of testosterone deficiency, which can have large ramifications and severe consequences.”

1. Patel P, Fantus R, Lokeshwar S, et al. Trends in Serum Testosteron Levels Among Adolescent and Young Adults Men in the United State. Presented at: 2020 AUA Virtual Experience; May 15, 2020. Abstract MP78-01.

The decline in total testosterone was observed even among men with normal body mass index.

Author | Kristie L. Kahl

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Cabozantinib combo induces clinical activity in advanced ccRCC

Novel BiTE immuno-oncology therapy appears safe with preliminary efficacy in mCRPC

Olaparib significantly improves OS in mCRPC subgroup

Testosterone levels show steady decrease among young US men