The combination of atezolizumab (Tecentriq) and cabozantinib (Cabometyx) elicited encouraging responses, marked by an unprecedented disease control rate (DCR), in previously treated patients with locally advanced or metastatic castration-resistant prostate cancer (mCRPC), but most strikingly in patients with high-risk features, according to findings from cohort 6 of the phase 1b COSMIC-021 trial (NCT03170960).

“We’re seeing an effective combination based on solid laboratory rationale, which is resulting in exciting responses and a really compelling DCR. We have not seen this kind of DCR with any immunotherapy combinations to date, and these patients are on this treatment regimen for approximately 6 months, which is remarkable given the age of this patient population,” said lead study author Neeraj Agarwal, MD.

“This is an elderly cohort of patients with metastatic prostate cancer that progressed on novel hormonal therapy, and these responses are durable. If you put all of that together, we are looking at a very promising combination which has real potential to make a meaningful difference in our patients’ lives,” Agarwal added.

Among 132 patients, all of whom had received prior enzalutamide (Xtandi) and/or abiraterone acetate (Zytiga), and 101 (77%) of whom had high-risk disease, the investigator-assessed objective response rate (ORR) among all patients was 23%; the investigator-assessed ORR in high-risk patients was 27%.

At a median follow-up of 15.2 months (range, 5.7-33.9), the median progression-free survival (PFS) per independent review was 5.7 months in the overall population vs 6.8 months in high-risk patients. The median overall survival (OS) was 18.4 months in both the overall and high-risk populations.

Among high-risk patients, the DCR was 88% per investigator assessment; it was 84% per blinded independent central review assessment.

, Agarwal, professor of medicine, Presidential Endowed Chair of Cancer Research, director, Genitourinary Oncology Program and the Center of Investigational Therapeutics, Huntsman Cancer Institute, University of Utah, expanded on the significance of the findings from the COSMIC-021 trial in mCRPC.

: Could you provide some background on cohort 6 of the COSMIC-021 trial?

: We started the COSMIC-021 trial approximately 4 years ago. The trial was started as a multi-cohort, phase 1 trial where the combination of cabozantinib and atezolizumab was being tested in multiple tumor types. One of those cohorts included patients with mCRPC. The eligibility criteria were very stringent in that patients had to have disease progression on at least 1 novel hormonal therapy and had to have progressive, soft tissue metastatic disease. Patients with progressive soft tissue metastasis will show disease progression in 6 weeks or in 3 months. We evaluated the combination of cabozantinib and atezolizumab based on robust preclinical data and the observation that cabozantinib, which creates an immunopermissive atmosphere in the tumor microenvironment, may be synergistic with atezolizumab, which is a PD-L1 inhibitor.

What was striking about the efficacy results?

We started with 30 patients and, based on the preliminary efficacy signals and tolerability signals, we expanded the cohort to 132 patients. At the 2021 ESMO Congress, I had the honor of presenting the data from these 132 patients. What we saw was really striking. All patients had disease progression on enzalutamide or abiraterone. In fact, almost half of the patients had disease progression on both drugs; 25% of patients had received docetaxel for metastatic castration-sensitive prostate cancer, which was allowed. All these patients had progressive measurable disease.

We defined our high-risk population as patients who had soft tissue metastasis and visceral [metastasis], such as [in the] liver, lung, and so on, and distal lymph node metastasis. These patients could not have had metastasis below the aortic bifurcation. Patients had to have metastases in the lymph nodes, mediastinum, supraclavicular area, axillary area, and so on. We know that wherever we see liver metastasis or visceral metastasis, or metastasis in the mediastinal lymph nodes, that those patients usually have poor prognosis compared with patients who do not have such metastasis.

Investigator-assessed response was the primary end point of the study. The investigator-assessed response by RECIST v1.1 criteria was 23% overall and 27% in patients who had these high-risk features, so visceral metastasis or soft tissue metastasis in the lymph nodes and the distant lymph nodes. Remarkably, the patients who had these aggressive features had better responses with cabozantinib and atezolizumab.

We also decided to have independent radiology assessment for the sake of stringency. Overall, the objective response was 15% vs 19% in the patients with high-risk disease. However, the DCRs, whether they were assessed by investigator or independent radiology, were higher than 80% across all subsets.

Among patients with visceral metastasis or distant lymph node metastasis and measurable disease, if you look at independent radiology assessment, the PFS, which was a secondary end point, was 6.8 months in this high-risk subset. In other patients, it was approximately 6 months. In this patient population, the median duration of therapy was approximately 6 months.

Was the safety profile of the combination at all concerning?

We saw grade 3/4 adverse effects [AEs] in 55% of patients, but most of them were altered taste, fatigue, and diarrhea, which are hallmarks of TKI-related AEs. Grade 4 AEs only occurred in 4% of patients, so most of the AEs are manageable with dose reduction or symptom management.

If you look at immune-related AEs [irAEs], less than 17% of patients received high-dose steroids for irAEs. Many of my patients got started on high-dose [steroids], but then we realized [the AEs were because of] cabozantinib, so we didn’t continue the steroids. We are not seeing autoimmune AEs of any significant prevalence in this patient population. We didn’t see any new safety signals. Cabozantinib plus nivolumab [Opdivo] and lenvatinib [Lenvima] plus pembrolizumab [Keytruda] are already approved in metastatic renal cell carcinoma and endometrial cancer, with lenvatinib/pembrolizumab, so oncologists are used to dealing with the [AEs of a TKI/immunotherapy] combination now.

Will the combination be taken forward into a phase 3 trial to confirm the activity that has been reported to date?

I am very happy to share that we have already started the phase 3 trial, the CONTACT-02 trial (NCT04446117), which is already accruing patients worldwide and accruing well. I’m really hoping that the trial, which is randomizing patients to cabozantinib plus atezolizumab vs a second novel hormonal therapy, finishes accrual soon and shows positive results, so that we can offer this exciting combination to our patients outside of a trial.

Agarwal N, McGregor BA, Maughan BL, et al. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of expanded cohort 6 of the COSMIC-021 study. Presented at: 2021 ESMO Congress. September 16-21, 2021; virtual. Abstract LBA24.

Articles

The combination of atezolizumab and cabozantinib elicited encouraging responses, marked by an unprecedented disease control rate, in previously treated patients with locally advanced or metastatic castration-resistant prostate cancer, but most strikingly in patients with high-risk features.

Atezolizumab/Cabozantinib Displays Promise in High-Risk mCRPC

Frontline immunotherapy resulted in improved progression-free survival and overall survival compared with sunitinib (Sutent) in patients with advanced renal cell carcinoma, according to data from a meta-analysis of 5 randomized trials presented during the 2021 ESMO Congress.

Investigators reported that all clinical trials included in the analysis reported an advantage to overall survival (OS) and progression-free survival (PFS) with an immunotherapy regimen compared with sunitinib (HR for OS, 0.71; 95% CI, 0.61-0.84; HR for PFS, 0.64; 95% CI, 0.51-0.82). Notably, the favorable-risk subgroup analysis indicated that no difference was observed in terms of OS between the treatment cohorts (HR, 1.07; 95% CI, 0.81-1.41) with a trend toward an advantage of immunotherapy for PFS (HR, 0.74; 95% CI, 0.46-1.19).

Due to recent evidence indicating that this patient population may experience an improved prognosis after being treated with immunotherapy, investigators launched the meta-analysis to evaluate the safety and efficacy of first-line immunotherapy compared with sunitinib in those with favorable-risk advanced RCC.

Investigators underwent a systemic search of PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and the evidence was assessed for quality. Survival hazard ratios were extracted for both the overall patient population and the favorable-risk subgroup.

Investigators used findings from 5 clinical trials, including the phase 3 CheckMate 9ER trial (NCT03141177), which examined nivolumab (Opdivo) plus cabozantinib (Cabometyx) versus sunitinib in previously untreated RCC; the phase 3 CheckMate214 trial (NCT02231749) which examined nivolumab plus ipilimumab (Yervoy); the phase 3 JAVELIN Renal 101 study (NCT02684006), which examined avelumab (Bavencio) plus axitinib (Inlyta); the phase 3 KEYNOTE-426 study (NCT02853331), which examined pembrolizumab (Keytruda) plus axitinib; and the phase 3 CLEAR trial (NCT02811861), which examined lenvatinib (Lenvima) plus pembrolizumab. The meta-analysis included a total of 1088 patients.

For the favorable-risk population in the CheckMate 9ER trial, investigators reported a hazard ratio (HR) of 0.84 for OS (95% CI, 0.35-1.97) and an HR of 0.62 (95% CI, 0.38-1.01) for PFS. Additionally, in the CheckMate214 trial, investigators reported HRs of 1.19 (95% CI, 0.77-1.85) and 1.65 (95% CI, 1.16-2.35) for OS and PFS, respectively, within the same patient population. The JAVELIN Renal 101 trial reported an HR of 0.81 (95% CI, 0.34-1.96) for OS and 0.63 for PFS (95% CI, 0.40-0.99) in the favorable-risk population. Moreover, the KEYNOTE-426 study reported HRs of 1.06 (95% CI, 0.60-1.86) and 0.79 (95% CI, 0.57-1.09) for OS and PFS, respectively. Lastly, the CLEAR trial reported HRs of 1.15 (95% CI, 0.55-2.40) and 0.41 (95% CI, 0.28-0.62) for OS and PFS, respectively, in this patient population.

Moreover, investigators noted that the safety profile appeared to be consistent with previously reported findings.

As the survival advantage garnered from an immunotherapy regimen has not yet been confirmed among those with favorable-risk advanced RCC, additional prospective trials containing a larger sample size and longer follow up are needed in order to confirm the benefit.

Manneh R, Lema M, Ibatá L, et al. Immunotherapy vs sunitinib as first-line treatment for advanced renal cell carcinoma in favourable risk patients. A meta-analysis of randomized clinical trials. Poster presented at 2021 European Society of Medical Oncology Annual Congress; September 16-21, 2021; virtual. Accessed September 16, 2021. Abstract 677P.

Frontline immunotherapy resulted in improved progression-free survival and overall survival compared with sunitinib in patients with advanced renal cell carcinoma; however, determining the benefit in those with favorable-risk disease must be examined further.

Frontline Immunotherapy Improves Survival in Advanced RCC, But Benefit to Be Determined for Favorable-Risk Subset

Patients with clear cell renal cell carcinoma who received the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) over sunitinib (Sutent) showed a benefit in adjusted overall survival and type and timing of subsequent therapy in a second interim analysis of the phase 3 KEYNOTE-426 study (NCT02853331).

Rustem Gafanov, MD, a principal investigator at the Russian Scientific Center of Roentgenoradiology, Moscow, Russian Federation, and colleagues, reported the findings during the 2021 European Society of Medical Oncology Congress.

Using a 2-stage estimation (TSE) model, investigators determined the effect, called the acceleration factor, of subsequent anticancer therapy for patients in KEYNOTE-426 (stage 1). In stage 2, survival time was determined after patients received the combination treatment of pembrolizumab and axitinib vs sunitinib. Survival time was adjusted multiplicatively by the acceleration factor that was determined in stage 1 of the trial. The investigators report that patients were assumed to be at a similar stage of disease in stage 1, ie, TSE model without recensoring.

At the data cutoff of January 21, 2021, 861 patients were randomly assigned to receive either pembrolizumab plus axitinib or sunitinib. There were 432 patients assigned to the combination arm and 429 were treated; there were 429 patients assigned to the monotherapy arm, with 425 patients receiving treatment.

In the combination arm, 18 (4.2%) patients completed treatment, 62 (14.5%) patients had ongoing treatment, and 349 (81.4%) patients discontinued. In the monotherapy arm, 40 (90.4%) patients had ongoing treatment and 385 (90.6%) had discontinued.

At the median follow-up of 42.8 months (range, 35.6-50.6), 204 patients in the combination arm received subsequent treatment with 3 who completed the regimen; there were 201 patients who discontinued treatment. Among those who discontinued, 150 patients demonstrated radiographic progressive disease (PD), 31 reported adverse events (AEs), and 8 patients decided to discontinue. There were 225 patients who did not receive subsequent treatment, with 15 completing the regimen, 62 had ongoing treatment, and 148 patients who discontinued. Reasons for discontinuing included radiographic PD (n = 64), AEs (n = 52), and 11 patients decided to discontinue.

In the monotherapy arm, 281 patients received subsequent treatment. Among those, 280 discontinued treatment. There were 192 patients who discontinued because of radiographic PD, 48 patients discontinued due to AEs, and 14 patients decided to discontinue. In this arm, 145 patients did not receive subsequent treatment, with 40 patients receiving ongoing treatment and 105 patients who discontinued. Reasons for discontinuing included radiographic PD (n = 51), AEs (n = 30), and patient’s decision (n = 11).

In the combination arm, median OS was 45.7 months (95% CI, 43.6-not reached) and in the monotherapy arm, median OS was 40.1 months (95% CI, 34.3-44.2). Patients in the combination arm had a 27% lower risk of death compared with the monotherapy arm (HR, 0.73; 95% CI, 0.60-0.88). Median PFS was 15.7 months in the combination arm (95% CI, 13.6-20.2) compared with 11.1 months in the monotherapy arm (95% CI, 8.9-12.5). Patients in the combination arm had a 32% lower risk of death (HR, 0.68; 95% CI, 0.58-0.80). Patients in the combination arm had an overall response rate (ORR) of 60.4% (95% CI, 55.6%-65.1%) compared with the monotherapy arm of 39.6% (95% CI, 35.0%-44.4%).

Baseline characteristics were similar for both arms. Average age was 61 years and 71.6% of participants were male in the combination arm (n = 204) compared with 77.6% in the monotherapy arm (n = 281). Regarding PD-L1 status, combined positive score (CPS) greater than 1 was 58.3% in the combination arm vs 61.6% in the monotherapy arm. CPS less than 1 was 38.7% in the combination arm vs 34.2% in the monotherapy arm. Overall, 47.6% of patients who received the combination treatment went on to receive subsequent systemic treatment of any type compared with 66.1% of patients who received monotherapy.

Among patients who received subsequent anticancer therapy with a PD-1/PD-L1 inhibitor, 21.6% were treated with the combination (N = 432) and 74.4% were treated with monotherapy (N = 429). In the combination arm, 88.2% of patients received any VEGF/VEGFR inhibitor compared with 68.7% in the monotherapy arm. Treatment with an agent other than PD-1/PD-L1 or VEGF/VEGFR inhibitors included everolimus (Afinitor; combination arm, 26.0% vs monotherapy arm, 13.%), ipilimumab (Yervoy; 3.9% vs 7.5%, respectively), and other (7.4% vs 5.3%).

In all patients who received subsequent therapy, median time to first subsequent therapy was 15.4 months (range, 0.8-44.9) in the combination arm compared with a median of 11.6 months (range, 0.2-45.3) in the monotherapy arm. Time to receive any PD-1/PD-L1 checkpoint inhibitor was a median of 25.2 months (range, 1.6-43.7) in the combination arm compared with a median of 14.0 months (range, 0.5-45.6) in the monotherapy arm. Time to receive any VEGF/VEGFR inhibitor was a median of 15.3 months (range, 0.8-44.9) in the combination arm compared with 14.6 months (range, 0.2-44.0) in the monotherapy arm. Time to any other treatment was 19.6 months (range, 3.5-46.5) in the combination arm compared with 16.0 months (range, 1.4-38.9) in the monotherapy arm.

The investigators concluded that patients in the combination arm received less frequent PD-1/PD-L1 inhibitor therapy vs the patients in the monotherapy arm. Patients who received the combination received more frequent VEGF/VEGFR therapy vs patients in the monotherapy arm. They noted that long-term OS with adjusted analysis was similar to the first interim analysis,

 in which few patients received subsequent therapy. These results, along with the first interim analysis, continue to support the use of pembrolizumab/axitinib over sunitinib in the first-line setting.

Gafanov R, Powles TB, Bedke J, et al. Subsequent therapy following pembrolizumab + axitinib or sunitinib treatment for advanced renal cell carcinoma (RCC) in the phase III KEYNOTE-426 study. Presented at: 2021 European Society of Medical Oncology. September 16-21, 2021. Abstract 669P. Accessed September 16, 2021. 

Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

Patients with clear cell renal cell carcinoma who received the combination of pembrolizumab and axitinib over sunitinib showed a benefit in adjusted overall survival and type and timing of subsequent therapy in a second interim analysis of the phase 3 KEYNOTE-426 study. 

Pembrolizumab/Axitinib Combo Demonstrates Long-Term OS Benefit in Clear Cell RCC

The 2021 ESMO Congress priority report focuses on updates in genitourinary cancers presented at the virtual conference, held September 16 to 21, 2021. 

2021 ESMO Congress: Genitourinary Cancers | Supplements and Featured Publications

Atezolizumab/Cabozantinib Displays Promise in High-Risk mCRPC

Frontline Immunotherapy Improves Survival in Advanced RCC, But Benefit to Be Determined for Favorable-Risk Subset

Pembrolizumab/Axitinib Combo Demonstrates Long-Term OS Benefit in Clear Cell RCC