Jason M. Broderick

According to findings from the phase 1b COSMIC-021 trial presented at the 2020 ASCO Virtual Scientific Program, cabozantinib (Cabometyx) and atezolizumab (Tecentriq) demonstrated clinically meaningful activity in patients with metastatic castration-resistant prostate cancer (mCRPC), including those with high-risk clinical features.

In a cohort of patients with mCRPC, the combination elicited an overall response rate (ORR) of 32%. Among 44 total patients, there were 3 complete responses and 11 partial responses. Twenty-one patients had stable disease, 8 patients had progressive disease, and data were not available for 1 patient. The disease control rate was 80%.

The median time to response was 1.6 months (range, 1-7) and the median duration of response was 8.3 months (range, 2.8-12.5+). Of note, the ORR was 33% in a subgroup of 36 patients with high-risk clinical features, which included those with visceral metastases and/or extra-pelvic lymph node metastases.

“The combination of cabozantinib and atezolizumab demonstrated a tolerable safety profile and clinically meaningful activity in men with mCRPC,” said lead study investigator Neeraj Agarwal, MD, professor, Huntsman Cancer Center, University of Utah. “[The mCRPC cohort] is being further expanded, and cohorts evaluating the contribution of cabozantinib and atezolizumab have been initiated. Further evaluation of cabozantinib and atezolizumab in mCRPC in a phase 3 trial is planned.”

Agarwal also noted that, “the combination treatment was associated with an increase in the number of activated cytotoxic T cells with concomitant decrease in immunosuppressive cells in peripheral blood.”

The multicenter, open-label, phase 1b COSMIC-021 trial is evaluating the combination of atezolizumab and cabozantinib in patients with locally advanced or metastatic solid tumors. Agarwal shared data for the first 44 patients enrolled in the mCRPC cohort. Prior treatment with docetaxel was permitted for those who had hormone-sensitive disease.

The median follow-up was 15.8 months (range, 9-23). Seventy-seven percent of the patients were white and 4.5% were black. Half of the patients had an ECOG performance status of 0 and the other half had a status of 1. Thirty-six (82%) patients had high-risk mCRPC, which was defined as having visceral and/or extra-pelvic lymph node metastases; 15 patients (34%) had visceral metastases and 27 (61%) had extra-pelvic lymph node metastases. Metastatic sites included lymph node (80%), bone (45%), lung (14%), liver (14%), adrenal gland (9%), and other (23%).

Twenty-five patients (57%) had a Gleason score ≥8 at diagnosis. Moreover, 12 patients (27%) received prior docetaxel for metastatic castration-sensitive disease, and all 44 patients had received prior novel hormonal therapy, including abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa). The median time between most recent systemic therapy and enrollment was 1.3 months. Overall, 70% of patients had prior radiotherapy and 80% of patients had prior surgery for prostate cancer.

Cabozantinib was administered orally at 40 mg once daily and intravenous atezolizumab was given at 1200 mg every 3 weeks. The primary end point was ORR.

Regarding biomarkers, Agarwal said, “Preliminary data do not suggest an association between PD-L1 expression and antitumor activity.”

The rate of grade 3/4 adverse events (AEs) was 59%; treatment-related grade 3/4 AEs occurring in at least 5% of patients were fatigue (7%), diarrhea (7%) and hyponatremia (7%).

Immune-related grade 3/4 AEs occurred in 4 patients and AEs led to cabozantinib dose reductions in 19 patients. In 4 patients, there were AEs unrelated to disease progression leading to both cabozantinib and atezolizumab discontinuation. One treatment-related grade 5 AE of dehydration was reported in a 90-year-old patient with a 6-month history of heart failure.

Cabozantinib is currently indicated for the treatment of patients with advanced RCC, as well as for the treatment of patients with hepatocellular carcinoma (HCC) who received prior treatment with sorafenib (Nexavar). Atezolizumab has approved indications in urothelial carcinoma, lung cancer, metastatic triple-negative breast cancer, and HCC.

Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: Results of cohort 6 of the COSMIC-021 study. J Clin Oncol 38: 2020 (suppl; abstr 5564). doi: 10.1200/JCO.2020.38.15_suppl.5564.

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According to findings from the phase 1b COSMIC-021 trial presented at the 2020 ASCO Virtual Scientific Program, cabozantinib and atezolizumab demonstrated clinically meaningful activity in patients with metastatic castration-resistant prostate cancer, including those with high-risk clinical features.

Clinically Meaningful Activity Observed With Combination Cabozantinib and Atezolizumab in mCRPC

Encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) continued to show an overall survival benefit compared with cetuximab plus irinotecan-based regimens as treatment of patients with 

-mutated metastatic colorectal cancer (mCRC) in the updated findings from the phase 3 BEACON CRC clinical trial.


A posthoc updated analysis presented during the 2020 ASCO Virtual Scientific Program showed that at a median follow-up of 12.8 months, the median OS was 9.3 months with encorafenib/cetuximab compared with 5.9 months in the control arm (HR, 0.61; 95% CI, 0.48-0.77). The median OS with the triplet of encorafenib/cetuximab plus binimetinib was also 9.3 months (HR vs control, 0.60; 95% CI, 0.47-0.75). For both the doublet and triplet regimens, the OS benefit was maintained versus the control arm across all key subgroups, including those defined by use of prior irinotecan, microsatellite instability (MSI) status, and number of prior regimens.


The objective response rate (ORR) was 27% with the triplet, 20% with the doublet, and 2% in the control arm. The ORR with the triplet comprised a complete response (CR) rate of 4% and a partial response (PR) rate of 23%. An additional 48% of patients had stable disease, while 11% of patients had progressive disease and 14% were not evaluable for response. Among patients who received the doublet of encorafenib and cetuximab, the ORR comprised a CR rate of 3% and a PR rate of 16%. Another 56% of patients had stable disease, 10% had progressive disease, and 15% were not evaluable for response.

The updated data showed that the median progression-free survival (PFS) was 4.5 months with the triplet compared with 1.5 months for the control arm (HR, 0.42; 95% CI, 0.33-0.53). The median PFS with the doublet was 4.3 months (HR vs control, 0.44; 95% CI, 0.35-0.55).

“In the BEACON CRC study, encorafenib plus cetuximab significantly improved OS, ORR, and PFS relative to standard of care in patients with 

 V600E–mutant mCRC, a population with historically dismal outcomes," said lead study author Scott Kopetz, MD, PhD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “With further follow-up after the primary analysis, the regimen of encorafenib plus cetuximab had similar overall efficacy as the encorafenib plus cetuximab with binimetinib regimen.”

Based on the BEACON CRC trial, the FDA approved the doublet regimen of encorafenib plus cetuximab in April 2020 for the treatment of adult patients with mCRC with a 

 V600E mutation, as detected by an FDA-approved test, after prior therapy.

BEACON CRC was an international open-label phase 3 trial that enrolled 665 patients with 

 V600E–mutated mCRC whose disease had progressed after 1 or 2 prior regimens. Patients had an ECOG performance status of 0 or 1 and no prior exposure to an EGFR inhibitor.

After a safety lead-in, patients were randomly assigned in a 1:1:1 ratio to the triplet of encorafenib, binimetinib, and cetuximab (n = 224); the doublet of encorafenib and cetuximab (n = 220); or the investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan; n = 221). At the time of analysis, 13% of patients in the triplet arm and 14% in the doublet arm remained on treatment compared with 3% in the control arm.

Baseline characteristics were “overall reasonably balanced” among the 3 arms, according to Kopetz. “Importantly, MSI-high status accounted for between 5% and 10% of the patients. Two-thirds of the patients had 1 prior line of therapy, with one-third of patients having more than 1 line,” noted Kopetz.

Updated safety data showed that grade ≥3 adverse events and laboratory abnormalities were consistent with the previously reported safety profile for the treatments. “It’s notable that the encorafenib/cetuximab/binimetinib arm had slightly higher rates of GI toxicity, [as well as higher rates of anemia as indicated] by low hemoglobin in the triplet arm that was not seen in the [doublet arm]. [Low hemoglobin] is associated with the known safety profile of a MEK inhibitor,” said Kopetz.

Findings from the primary analysis of the BEACON CRC study were published in 2019 in the 

and showed that, after a median follow-up of 7.8 months, the median OS was 9.0 months in the triplet arm versus 5.4 months in the control group (HR, 0.52; 95% CI, 0.39-0.70; 

 The median OS in the doublet arm was 8.4 months (HR vs control, 0.60; 95% CI, 0.45-0.79; 

 = .0003).

Both the triplet (HR, 0.38; 95% CI, 0.29-0.49; 

 <.001) and the doublet (HR, 0.40; 95% CI, 0.31-0.52; 

 <.001) significantly improved PFS over the control arm. The median PFS was 4.3 months in the triplet arm, 4.2 months with the doublet, and 1.5 months in the control arm. The ORRs were 26% with the triplet, 20% with the doublet, and 2% in the control arm.

Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for 

 V600E metastatic colorectal cancer: Updated survival results from a randomized, three-arm, phase III study versus choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract 4001.

Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in 

Encorafenib plus cetuximab with or without binimetinib continued to show an overall survival benefit compared with cetuximab plus irinotecan-based regimens as treatment of patients with BRAF-mutated metastatic colorectal cancer in the updated findings from the phase 3 BEACON CRC clinical trial.

Encorafenib/Cetuximab Combos Sustain OS Benefit in BRAF+ Metastatic Colorectal Cancer

Treatment with idecabtagene vicleucel (ide-cel; bb2121) led to responses in 73% of heavily pretreated patients with relapsed or refractory multiple myeloma, and complete responses (CRs) in 33%, according to topline findings from the pivotal phase 2 KarMMA trial.

Data shared during the 2020 ASCO Virtual Scientific Program demonstrated a median duration of response (DOR) of 10.7 months, and amedian progression-free survival (PFS) of 8.8 months (95% CI, 5.6-11.6).

“Ide-cel demonstrated frequent, deep, and durable responses in heavily pretreated, highly relapsed/refractory patients with myeloma,” said Nikhil C. Munshi, MD, director of Basic and Correlative Science, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, and professor of Medicine, Harvard Medical School. “Overall, ide-cel provides an attractive option for the treatment of patients with triple-class exposed relapsed/refractory myeloma.”


In March 2020, Bristol Myers Squibb and bluebird bio, Inc., the codevelopers of ide-cel, submitted a Biologics License Application (BLA) to the FDA for the use of the BCMA-targeting chimeric antigen receptor (CAR) T-cell therapy as a treatment for adult patients with multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

However, earlier this month, the FDA issued a Refusal to File letter to the companies regarding the BLA. In its initial review, the agency concluded that additional information was needed for the Chemistry, Manufacturing and Control module of the BLA. The FDA did not ask for any further clinical or nonclinical data according to the companies, which plan to resubmit the application by the end of July of this year.

The phase 2 KarMMA trial (NCT03361748) included 128 patients with relapsed/refractory multiple myeloma who received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

The median age was 61 months (range 33-78), 35% of patients had high-risk cytogenetics, 51% had high tumor burden, 39% had extramedullary disease, and 85% had ≥50% tumor BCMA expression. ECOG performance status was 0 (45%), 1 (53%), or 2 (2%). R-ISS disease stage was I (11%), 2 (70%), or III (16%). Patients had received a median of 6 (range, 3-16) prior antimyeloma regimens.

Ninety-four percent of patients had received 1 prior autologous stem cell transplant, and 34% had received more than 1. Eighty-eight percent of patients received bridging therapies during CAR T-cell manufacturing; however, only 4% of patients responded to the treatment. Regarding refractory status, 94% of patients were refractory to anti-CD38 antibodies and 84% were triple refractory.

Patients were treated at CAR+ T cell doses of 150 x 10

(n = 54). The median follow-up was 18 months, 15.8 months, and 12.4 months, respectively. Across all patients, the median follow-up was 13.3 months. The primary end point was objective response rate (ORR), with secondary end points including CR, DOR, PFS, overall survival (OS), and quality of life.

Across all patients, the 73% ORR (95% CI, 65.8%-81.1%; 

 <.0001) included a 33% CR rate (95% CI, 24.7-40.9; 

 <.0001), a 20% very good partial response rate, and a 21% partial response rate. The overall CR rate comprised 26% of patients who achieved a CR/stringent CR (sCR) and were minimal residual disease (MRD)-negative, and 7% of patients who achieved a CR/sCR but who did not have MRD data. The median time to first response was 1 month (range, 0.5-8.8) and the median time to CR was 2.8 months (range, 1-11.8).

“Durable responses were observed across all doses,” said Munshi. At the dose of 450 x 10

 CAR+ T cells, the ORR was 82% and the CR/sCR rate was 39%.

Clinically meaningful efficacy in terms of ORR was observed across subgroups, irrespective of age, risk categorization, tumor burden, BCMA expression level, extramedullary disease, triple-refractory status, penta-refractory status, and bridging therapy.

PFS increased as the target dose increased. At the 450 x 10

 CAR+ T-cell dose, the median PFS was 12.1 months (95% CI, 8.8-12.3). The median PFS also increased by depth of response with a median of 20.2 months (95% CI, 12.3–not evaluable) among patients who achieved a CR/sCR.

Munshi said the survival data are immature. At the time of the analysis, the median OS was 19.4 months (95% CI, 18.2–not evaluable) and the 1-year OS rate was 78%.

“Cytokine release syndrome (CRS) frequency increased with dose but was mostly low-grade,” said Munshi. Overall, 84% of patients had ≥1 CRS event, with the majority (78%) being grade 1/2. There were 5 cases of grade 3 CRS, 1 case of grade 4, and 1 case of grade 5. The median time to onset of CRS was 1 day (range, 1-12), and the median duration of CRS was 5 days (range, 1-63). Fifty-two percent of patients received tocilizumab (Actemra) for CRS management, and 15% of patients received corticosteroids.

“Neurotoxicity was mostly low grade and was similar across target doses,” said Munshi. Overall, 18% of patients had ≥1 neurotoxicity event. There were 19 cases of grade 1/2 neurotoxicity and 4 cases of grade 3. There were no grade 4 or 5 incidents. The median time to onset of neurotoxicity was 2 days (range, 1-10), and the median duration was 3 days (range, 1-26). Two percent of patients received tocilizumab for neurotoxicity, and 8% of patients received corticosteroids.

The other significant adverse event, according to Munshi, was cytopenia—91% of patients had any grade neutropenia (89% grade ≥3), and 63% (52% grade ≥3) had any grade thrombocytopenia. “The median time to recovery of grade ≥3 neutropenia and thrombocytopenia was 2 months and 3 months, respectively,” said Munshi.

There were 5 deaths within 8 weeks of ide-cel infusion—2 following myeloma progression and 3 from AEs (CRS, aspergillus pneumonia, and GI hemorrhage). There was also 1 other AE-related death (CMV pneumonia) that occurred within 6 months, in the absence of myeloma progression.

Munshi NC, Anderson Jr LD, Jagannath S, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract 8503.

“Ide-cel demonstrated frequent, deep, and durable responses in heavily pretreated, highly relapsed/refractory patients with myeloma. Overall, ide-cel provides an attractive option for the treatment of patients with triple-class exposed relapsed/refractory myeloma."

High Rate of Responses Seen With Ide-cel in Heavily Pretreated Myeloma

Dabrafenib (Tafinlar) plus trametinib (Mekinist) on a continuous dose led to improvements in progression-free survival (PFS) as treatment of patients with 

-mutant advanced melanoma compared with intermittent dosing of dabrafenib/trametinib, according to data from the phase II SWOG S1320 clinical trial presented during the 2020 virtual annual meeting of the American Association for Cancer Research.

The findings from this study showed that the median PFS was 9.0 months in the continuous arm versus 5.5 months in the intermittent arm (HR, 1.36; 80% CI, 1.10-1.66; 

“The PFS advantage in favor of continuous dosing was observed in younger and older patients, men and women, patients with and without prior immune checkpoint inhibitor therapy, and in patients with normal and elevated baseline LDH levels,” said Alain Algazi, MD, an associate professor in the Department of Medicine at University of California San Francisco and the study chair with SWOG Cancer Research Network, which led the research.

The outcome of the trial was the opposite of the study hypothesis. Based on positive preclinical signals in mouse models, the investigators hypothesized that intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib could overcome acquired resistance to BRAF inhibitors and improve PFS in this patient population.

The open-label phase 2 SWOG S1320 trial enrolled 206 patients with advanced 

 V600E/K melanoma over 5 years at 68 clinical sites, including some community practices. Baseline characteristics were well balanced between the 2 treatment arms. The median age was 58 and 62 in the continuous and intermittent arms, respectively. Fifty-nine percent and 69% of patients were male, and 98% and 97% of patients were white in the 2 arms, respectively. Almost all patients in each arm had an ECOG performance status of 0 or 1. Seventy percent of patients in each arm had no prior exposure to an immune checkpoint inhibitor.

All patients received an 8-week lead-in course of continuous dosing after which patients who achieved an objective response or stable disease were randomized to continuous (n = 105) or intermittent (n = 101) dabrafenib plus trametinib. The intermittent schedule was 3 weeks off/5 weeks on. Algazi noted that following the 8-week lead-in period, “There were no statistically significant differences in the initial tumor response between the 2 treatment arms.”

In the continuous arm, 21 patients remained on treatment at the time of the analysis, with 84 patients having discontinued, primarily due to disease progression (n = 54). In the intermittent cohort, 17 patients were still on treatment, with 84 discontinuing, again primarily due to progression (n = 62).

Although the study was not powered to detect differences in overall survival (OS), Algazi reported that there was no significant difference in survival observed, with a median OS of 29.2 months in each arm. This lack of OS difference extended across all key patient subgroups.

However, Algazi noted that, “The shorter period of disease control in intermittent-dosed patients appeared to be offset after disease progression in S1320.” Following disease progression, there was a statistically significant OS improvement favoring the intermittent dosing arm (HR, 0.76; 80% CI, 0.78-1.00; 

Addressing potential explanations for this outcome, Algazi discussed subsequent therapy, explaining that investigator-reported data showed that about half of the patients in each arm received an immunotherapy agent post-S1320. “There was no significant difference in exposure to anti–CTLA-04 or anti–PD-1 antibodies following treatment on S1320 between the 2 study arms.” Thus, subsequent immunotherapy would not explain the OS difference.

Additionally, he also recalled that since “30% of patients in each study arm were exposed to immune checkpoint inhibitors prior to study enrollment, any latent effect of prior exposure to these agents is unlikely to explain differences in post-study survival.”

Regarding all of the OS data, Algazi cautioned, “While interesting, OS or post-progression survival findings should be considered hypothesis-generating at this point.”

Discussed the safety data in the S1320 trial, Algazi said, “We observed similar toxicity in both arms, despite decreased drug exposure in the intermittent arm.”

The most common treatment-related adverse events were chills, fatigue, and fever. Grade 1/2 chills occurred in 30 patients in the continuous arm versus 32 patients in the intermittent arm, grade 1/2 fatigue occurred in 50 patients in both arms, and grade 1/2 fever occurred in 37 patients in the continuous arm versus 31 patients in the intermittent arm.

There was 1 case each of grade 3 chills in both arms. Grade 3 fatigue occurred in 8 patients and 3 patients in the continuous and intermittent arms, respectively. There were 6 patients with grade 3 fever in the continuous arm and 1 patient in the intermittent arm had grade 4 fever.

Algazi offered several potential explanations for why the trial was a “negative” trial, one being that there was less drug exposure in patients randomized to the intermittent-dosing arm. “But this was also true in the animal model of vemurafenib,” he noted, “And if this is a major differentiating factor, we have to assume that any benefit of intermittent therapy could not offset decreased drug exposure.”

He also offered that, “There are preclinical data suggesting that a rapid decrement in drug levels is required to get effective tumor killing in drug-addicted cells. The long half-life of trametinib—4 days in humans—may have precluded the rapid decrement in exposure required to get an effective drug withdrawal.”

A third explanation postulated by Algazi was that in these patients, non-MAPK resistance pathways may be the real issue. “It is possible that mechanisms that can be addressed with intermittent dosing are not the predominant mechanisms of treatment resistance in a broad human patient population.”

And the final hypothesis Algazi gave for the unexpected study outcome was that “it may take longer than 8 weeks for resistant clones to develop.”

Also commenting on the outcomes in a press release was Antoni Ribas, MD, PhD, the senior leader on the trial, the former chair of the melanoma research committee at SWOG, and the AACR president. He is also a professor of medicine at the David Geffen School of Medicine at the University of California Los Angeles, director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program, and director of the Parker Institute for Cancer Immunotherapy Center at UCLA.

"The idea of prescribing therapy intermittently made sense," Ribas stated. "Cancer cells wouldn't have enough time to get used to it, and become resistant—a notion that was supported scientifically by well-conducted studies in the laboratory. This clinical study illustrates the importance of ultimately testing hypotheses in human patients, which is the underlying reason for the existence of NCI-funded groups like SWOG."

Algazi A, Othus M, Daud A, et al. SWOG S1320: improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma. Presented at: 2020 virtual annual meeting of the American Association for Cancer Research; April 27-28, 2020. Abstract CT013.

Continuous dosing improves progression-free survival for melanoma patients with common mutations. Posted April 27, 2020. https://bit.ly/35c1zlS. Accessed April 27, 2020.

“The PFS advantage in favor of continuous dosing was observed in younger and older patients, men and women, patients with and without prior immune checkpoint inhibitor therapy, and in patients with normal and elevated baseline LDH levels."

Author | Jason M. Broderick

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