Hannah Slater

Immunotherapy with pembrolizumab (Keytruda) in combination with capecitabine-based chemotherapy and the VEGF inhibitor bevacizumab (Avastin), appeared tolerable as treatment of patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), showing a safety profile that expected with the drug, results from a phase study study show.

“With 2 responses, the study met interim analysis criteria to continue accrual, and tissue and blood-based immune correlatives are planned,” Andrea Grace Bocobo, BS, a medical student at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, said during a virtual poster presentation of the data during the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium.

This single-arm, open-label, single-site, phase 2 trial was designed to evaluate the safety, tolerability, and preliminary efficacy of pembrolizumab in combination with capecitabine and bevacizumab in patients with MSS mCRC. Patients with stable disease (SD) or progressive disease (PD) on prior fluoropyrimidine-based therapy were eligible for the study. Treatment consisted of the recommended phase 2 dose PO capecitabine on days 1-14 plus 200 mg pembrolizumab intravenously (IV) and 7.5 mg/kg bevacizumab IV on day 1 in 21-day cycles.

Of note, the study followed a Simon’s 2-stage design with a safety lead-in to confirm the recommended phase 2 dose for capecitabine and expansion cohorts. In the first stage, ≤ 1 response among 29 patients required trial suspension. Otherwise, 15 additional patients will be accrued for a total study cohort of 44 patients.

The safety lead-in confirmed a recommended phase 2 dose for capecitabine of 1000 mg/m2 PO BID.

At the planned interim analysis (April 2018 to September 2020), a total of 29 patients had been enrolled in the study, of whom 15 (52%) were female and 21 (72%) were white; the median age was 55 years (range 36-77 years). Additionally, 26 (90%) patients had PD on fluoropyrimidine-containing regimens and 24 (83%) patients had prior exposure to bevacizumab. The median prior lines of systemic therapy was 3 (range, 1-5).

As of the data cutoff of December 7, 2020, 3 (10%) patients remained on active treatment. The median time on treatment was 4 months (range 1-26 months) and 45% of patients were on treatment for ≥6 months.

Overall, no unexpected treatment-related adverse events (AEs) were reported, and no treatment-related AEs led to treatment discontinuation or death. Complete toxicity data was available for 26 off-treatment patients.

The most commonly reported adverse events (AEs) were palmar-plantar erythrodysesthesia (PPE; 62%) and fatigue (65%). Grade ≥3 related AEs occurred in 10 (38%) patients, including immune-related AEs of grade 3 dyspnea, hypophosphatemia, and pancreatitis in 1 patient each. Grade 3 hypertension also occurred in 2 patients and 1 patient had a grade 4 treatment-related AE of pneumoperitoneum; there were no grade 5 treatment-related AEs. Treatment related AEs which led to dose interruptions, reductions, or delays occurred in 15 (60%) patients, the most common being PPE in 13 (50%) patients.

Overall, per RECIST 1.1 criteria, 24 (83%) patients were considered evaluable, including 2 patients with a partial response (PR; 8%), 14 with SD (59%), and 8 (33%) with PD. Of the 5 patients considered unevaluable, 4 patients had discontinued treatment due to clinical progression prior to restaging and 1 patient had not yet completed restaging scans.

Of those with a PR, one patient had a time to response of 11 months and the other had a time to response of 2 months. Moreover, the first patients had 12 months until disease progression while the other had 15 months. The first patient was on treatment for 26 months and the second was on treatment for 17 months as of the cut-off date, though their treatment remains ongoing.

Notably, both patients with a PR had KRAS-mutant colon cancers, metastatic to liver, with progressive disease on prior fluoropyrimidine-based therapy.


Bocobo AG, Wang R, Behr S, et al. Phase II study of pembrolizumab plus capecitabine and bevacizumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Interim analysis. 

Articles

Immunotherapy with pembrolizumab in combination with capecitabine-based chemotherapy and the VEGF inhibitor bevacizumab, appeared tolerable as treatment of patients with microsatellite stable metastatic colorectal cancer, showing a safety profile that was expected with the drug, results from a phase 2 study show.

Safety of Pembrolizumab With Capecitabine and Bevacizumab Demonstrated in MSS mCRC

Statistically significant and clinically meaningful improvements in both progression-free survival (PFS) and overall survival (OS) were observed with the addition of tucatinib (Tukysa) to trastuzumab (Herceptin) and capecitabine (Xeloda) as treatment of patients with HER2-positive metastatic breast cancer, irrespective of the presence of brain metastases, according to findings from the HER2CLIMB study, which were presented during the 2020 ESMO Virtual Congress.

Notably, this combination has been approved by the FDA based on results from the primary analysis of this trial for the treatment of patients with and without brain metastases who have received 1 or more prior anti-HER2-based regimens in the metastatic setting.

“Taken together, this regimen not only provides meaningful clinical activity, but also maintains quality of life in patients with or without brain metastases,” Volkmar Mueller, head of the Oncology Outpatient Clinic at the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, said in a virtual presentation during the meeting.

The pivotal, randomized trial of tucatinib in combination with trastuzumab and capecitabine versus placebo in combination with trastuzumab and capecitabine enrolled patients with HER2-positive metastatic breast cancer who had received prior treatment with trastuzumab, pertuzumab (Perjeta), and T-DM1, had an ECOG performance status of 0 or 1, and who had a brain MRI at baseline. Including patients who were previously untreated, treated stable, and treated and progressing, 48% of patients had brain metastases at baseline.

Overall, 410 patients were randomized to the tucatinib arm and 202 to the placebo arm. Of the total cohort of 612 patients, 330 had data available for health-related quality of life (HRQoL) analyses, including 217 patients in the tucatinib arm and 113 patients in the placebo arm.

In patients treated with the tucatinib combination, 2-year OS was 45% (95% CI, 37-53) compared to 27% in the placebo combination arm (95% CI, 16-39). Moreover, median OS for the tucatinib arm was 21.9 months (95% CI, 18.3-31.0) versus 17.4 months in the placebo arm (95% CI, 13.6-19.9). In the total cohort of 612 patients, risk of death was reduced by 34% (95% CI, 0.50-0.88; 

The median duration of exposure was 7.3 months for those treated with the tucatinib combination (<0.1-35.1) and 4.4 months for those treated with the placebo combination (<0.1-24.0).

The primary end point of PFS by blinded independent central review was assessed in the first 480 patients enrolled. Overall, risk of progression or death was reduced by 46% (95% CI, 0.42-0.71; 

 < 0.001). Specifically in patients with brain metastases (n = 291), risk of progression or death was reduced by 52% (95% CI, 0.34-0.69; 

Notably though, benefit was observed in patients both with and without brain metastases.

Researchers also assessed HRQoL with protocol version 7, using the EQ-5D-5L which includes an EQ visual analog scale (VAS) and descriptive system (EQ-5D) of 5 health dimensions, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels which consist of no, slight, moderate, severe, or extreme problems.

Across all 5 EQ-5D-5L domains, the majority of patients in both arms reported only slight or no problems. Moreover, moderate, severe, or extreme problems that were reported were low and similar between the treatment arms. No clinically meaningful differences in HRQoL were seen between the 2 arms.

Overall, mobility and usual activities were maintained by patients throughout the course of treatment. There was also no change in pain and self-care categories reported throughout the treatment course. Further, there was no change in the anxiety/depression category throughout the course of treatment.

In addition, mean EQ-5D-5L VAS scores were similar between patients treated with the tucatinib combination and those treated with the placebo combination and were also stable throughout the duration of therapy. Decline on EQ-5D-5L domains and VAS scores were also not observed while patients were on therapy.

With regard to safety, the addition of tucatinib did not increase the percentage of patients who required hospitalization. Treatment-related adverse events (AEs) which resulted in hospitalization in ≥1% of patients in the tucatinib arm included diarrhea (3%), vomiting (2%), seizure (2%), and dyspnea (1%). All other events that led to hospitalization were less than 1%.

Mueller V, Paplomata E, Hamilton E, et al. Impact of Tucatinib on Health-Related Quality of Life in Patients with HER2+ Metastatic Breast Cancer with and without Brain Metastases. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 275O.

Statistically significant and clinically meaningful improvements in both progression-free survival and overall survival were observed with the addition of tucatinib to trastuzumab and capecitabine as treatment of patients with HER2-positive metastatic breast cancer, irrespective of the presence of brain metastases.

Survival Improved With Tucatinib Regimen in HER2-Positive Metastatic Breast Cancer

Patients with relapsed or refractory indolent non-Hodgkin lymphoma who were treated with the chimeric antigen receptor (CAR) T-cell therapy of axicabtagene ciloleucel (axi-cel; Yescarta) had high rates of complete response (CR) and demonstrated the agent's manageable safety profile, according to an interim analysis of the phase 2 ZUMA-5 study (NCT03105336) presented as part of the 2020 American Society of Clinical Oncology Virtual Scientific Program.



“Axi-cel yields high rates of response in indolent B-cell non-Hodgkin lymphoma,” Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute, said during a presentation of the data. “Although longer follow-up is needed, these responses appear to be durable amongst follicular lymphoma patients.”

Adults with relapsed or refractory follicular lymphoma (FL; grades 1-3a) and marginal zone lymphoma (MZL; nodal or extranodal) after ≥2 lines of therapy (including an anti-CD20 monoclonal antibody [mAb] with an alkylating agent), and an ECOG status of 0 or 1 were eligible for the study. Participants were leukapheresed and received conditioning chemotherapy followed by axi-cel infusion at 2 × 10

Of the 96 patients evaluable for efficacy, the objective response rate (ORR) was 93% (95% CI, 86%-97%) and the CR rate was 80% (95% CI, 71%-88%). The median time to first response was 1 month (range, 0.8-3.1). More specifically, patients with FL (n = 80) had an ORR of 95%, with an 81% CR rate, and those with MZL (n = 16) had an ORR of 81% with a 75% CR rate.

With a median follow-up of 15.3 months, the estimated duration of response (DOR) in all patients was 20.8 months, and 68% of patients with FL had an ongoing response as of the data cut-off. Moreover, the median PFS was 23.5 months (95% CI, 22.8 - not evaluable) in all patients, and the median overall survival (OS) was not reached. However, the 12-months OS rate was 94.3% (95% CI, 86.8-97.6) for all patients.

These interim results  suggest that axi-cel may be a promising approach for treating this patient population.

The primary endpoint of the study was ORR by central review. Key secondary endpoints included DOR, progression-free survival (PFS), OS, safety, and blood levels of cytokines and CAR T-cells.

As of December 16, 2019, 140 patients (FL, n = 124; MZL, n = 16) had received axi-cel with a median follow-up of 15.3 months (range, 1.9-28.8). The median age of the participants was 63 years of age (range, 34-79), 49% of patients were male, 52% had stage IV disease, 51% had ≥ 3 FLIPI, and 49% had high tumor bulk (GELF). Moreover, patients had a median 3 prior lines of therapy, 66% progressed < 2 years after initial anti-CD20 mAb-containing therapy (POD24), and 73% were refractory to the last prior treatment.

All of the study participants were evaluable for safety, and 119 patients (85%) experienced grade ≥ 3 adverse events (AEs). The most commonly observed AEs were neutropenia (34%) and anemia (22%). Additionally, grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 8% and 17% of patients, respectively. There were only 2 grade 5 AEs, including multisystem organ failure in the context of CRS (related to axi-cel) and aortic dissection (unrelated to axi-cel).

“Given the long natural history of these diseases, safety is of paramount importance,” Jacobson said. “The safety profile was manageable and reversible, and appeared to be at least similar to that of axi-cel in aggressive lymphomas.”

The median time to peak of anti-CD19 CAR T-cell levels after axi-cel infusion was 8 days (range, 8 - 371). Furthermore, anti-CD19 CAR T-cells were detectable at 18 months in most patients with evaluable samples (13/15 [87%]).

Notably, in patients with FL, peak CAR T-cell expansion was associated with both grade ≥3 CRS (

 = 0.0076). In addition, peak serum analyses across multiple immune programs were associated with grade ≥ 3 CRS, grade ≥ 3 neurologic events, or both in patients with FL.

“This may have implications for the possibility of outpatient therapy for this disease in the future,” said Jacobson.

“Axi-cel appears to be a promising therapeutic approach for patients with relapsed and refractory indolent B-cell non-Hodgkin lymphoma.”

Axi-cel is currently approved by the FDA as a treatment for adult patients with relapsed or refractory large B-cell lymphoma based on findings from the phase II ZUMA-1 trial.2 The agent is indicated specifically following 2 prior therapies for those with diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma (TFL).

Jacobson CA, Chavez JC, Sehgal AR, et al. Interim analysis of ZUMA-5: A phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL). Presented at: 2020 ASCO Virtual Scientific Meeting; May 29, 2020. Abstract 8008.

FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. FDA website. Published October 18, 2017. fda.gov/news-events/press-announcements/fda-approves-car-t-cell-therapy-treat-adults-certain-types-large-b-cell-lymphoma. Accessed May 30, 2020.

<< View more of Targeted Oncology's coverage from the 2020 ASCO Virtual Annual Meeting

Interim analysis of the ZUMA-5 study indicates that patients with relapsed or refractory indolent non-Hodgkin lymphoma who were treated with the chimeric antigen receptor T-cell therapy of axicabtagene ciloleucel had high rates of response and demonstrated the agent's manageable safety profile.

CAR T-Cell Therapy With Axi-Cel Holds Promise in R/R Indolent NHL

Findings from the phase 3 HERO trial show continued superiority of relugolix (Relumina) compared with leuprolide (Lupron) in patients with advanced prostate cancer. In a presentation during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, testosterone (T)-suppression was sustained through 48 weeks with relugolix, and there was also fast T-recovery after discontinuation, and a 50% reduction in major adverse cardiovascular events (MACE).

Additionally, relugolix achieved castration as early as day 4, suggesting the potential for this agent to become a new standard for T-suppression in this patient population.

“Relugolix is a novel, oral GnRH receptor antagonist that achieves both LH and FSH suppression to its direct inhibitory effect on the pituitary GnRH receptors,” Neal D. Shore, FACS, MD, medical director for the Carolina Urologic Research Center, said in a press release. “This direct inhibition does not result in a testosterone surge.”

The 48-week, global, pivotal phase III trial, which also published in 

, randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 fashion to receive either 120 mg of relugolix orally once daily after a one-time 360 mg loading dose or a 3-month depot injection of leuprolide acetate.

 Testosterone recovery was also evaluated in a subset of 184 patients.

The primary end point of the study was to achieve and maintain serum T-suppression to castrate levels (< 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at day 4 and day 15, profound castration (< 20 ng/dL) rates at days 4 and 15, PSA response rate at day 15, and FSH levels at week 24.

In order to be included in the study, patients had to have confirmed advanced prostate cancer, ≥1 years of androgen deprivation therapy (ADT), a serum PSA > 2.0 ng/mL, and an ECOG score of 0 or 1. Patients who were expecting to under chemotherapy or surgical therapy within 2 months of initiating ADT, had previous ADT for >18 months for previous systemic cytotoxic therapy for prostate cancer, had active liver disease, or severe cardiovascular risk conditions were excluded from the study.

Of the 624 patients randomized to the relugolix arm, 563 (90.2%) completed treatment compared to 276 of the 310 (89.0%) who were given leuprolide. Moreover, 59 of the 624 (9.5%) and 32 of the 310 (10.3%), respectively, terminated their treatment early. The remaining patients were randomized, but not treated.

The characteristics of the patients at baseline were well balanced between the 2 treatment groups. Moreover, 50.2% of the men enrolled had biochemical recurrence after definitive treatment for prostate cancer, 28.9% were enrolled in North America, and 11.5% were from Japan. More than 90% of the patients also had at least 1 cardiovascular risk factor.

Overall, 96.7% (95% CI, 94.9%-97.9%) of men treated with relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. Notably, the difference of 7.9% (95% CI, 4.1%-11.8%) demonstrated noninferiority (margin -10%) and superiority (

 < 0.0001) of relugolix to leuprolide. All key secondary endpoints tested also demonstrated superiority over leuprolide (

 < 0.0001).

In the subset of patients evaluated for testosterone recovery, median T-levels were 270.76 ng/dL in the relugolix group compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy.

In a prespecified analysis, the incidence of MACE was found to be lower in the relugolix group than in the leuprolide group (2.9% vs 6.2%, respectively). Otherwise, the safety and tolerability profiles of the 2 agents were generally similar. Adverse events (AEs) reported for >10% of patients treated with relugolix or leuprolide were hot flush (54.3% vs 51.6%, respectively), fatigue (21.5% vs 18.5%), constipation (12.2% vs 9.7%), diarrhea (12.2% vs 6.8%), arthralgia (12.1% vs 9.1%), and hypertension (7.9% vs 11.7%). Notably, AEs of diarrhea were of grade 1 or 2 and did not result in study discontinuation.

“Relugolix once daily was well tolerated with an adverse event profile consistent with T-suppression,” Shore said. “Most notably, the risk of major adverse cardiovascular events was 54% lower in the relugolix group compared to leuprolide.”

Furthermore, though oral treatments are now commonly used for men with advanced and castration-resistant prostate cancer, concerns remain about adherence to oral ther-apies. However, the investigators indicated that treatment adherence with oral relugolix was more than 99% and similar to that seen with injectable leuprolide.

“Relugolix is a novel, oral GnRH antagonist that has the potential to become a new standard for ADT in advanced prostate cancer,” Shore concluded.

1. Shore ND, George DJ, Saad F, et al. HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist versus leuprolide acetate for advanced prostate cancer. Presented at: 2020 ASCO Virtual Scientific Program. Abstract 5602.

2. Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. 

"Relugolix is a novel, oral GnRH antagonist that has the potential to become a new standard for ADT in advanced prostate cancer."

Hannah Slater | Authors

Articles

Safety of Pembrolizumab With Capecitabine and Bevacizumab Demonstrated in MSS mCRC

Survival Improved With Tucatinib Regimen in HER2-Positive Metastatic Breast Cancer

CAR T-Cell Therapy With Axi-Cel Holds Promise in R/R Indolent NHL

Relugolix May Replace Current Standard of Care for T-Suppression in Advanced Prostate Cancer