Courtney Marabella

Keytruda (pembrolizumab) plus chemotherapy improved survival outcomes in patients with previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (TNBC), with a PD-L1 combined positive score (CPS) of 10 or higher, according to findings from the phase 3 KEYNOTE-355 clinical trial.

Trial findings, which were presented at the 

, showed that the Keytruda/chemotherapy regimen led to an average overall survival of 23 months, which is higher than the average overall survival of 16.1 months in patients who received chemotherapy plus placebo. At 18 months, 58.3% of patients receiving the Keytruda combo were alive, compared with 44.7% in the chemotherapy group.

Progression-free survival, which is the time a patient lives before their disease gets worse, was longer in the immunotherapy group, too, at an average of 9.7 months compared with 5.6 months in the Keytruda and chemotherapy alone groups, respectively. At the 12-month mark, 39.1% of patients administered Keytruda/chemotherapy were still alive without disease progression, compared with 23% in the placebo/chemotherapy group.

Furthermore, a PD-L1 CPS of at least 10 was found to be a reasonable cut-off to define the population of patients expected to derive the most benefit from this regimen. PD-L1 CPS measures the amount of PD-L1 protein — which is targeted by checkpoint blockade drugs like Keytruda — that is present in an individual’s cancer. These findings showed that patients with PD-L1 scores of 10 or higher had enough of the protein for the therapy to work effectively.

“These results provide further support for pembrolizumab in combination with chemotherapy as the new standard-of-care treatment regimen for patients with locally recurrent, unresectable or metastatic TNBC whose tumors express a PD-L1 CPS of 10 or more,” lead study author Dr. Javier Cortés, the head of breast cancer and gynecological cancers at Hospital Universitario Ramón y Cajal, in Madrid said in a presentation of the data.

Keytruda is currently approved by the Food and Drug Administration (FDA) for use in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10 or greater) as determined by an FDA-approved test. The 

was based on earlier findings of the KEYNOTE-355 trial.

In the KEYNOTE-355 trial, the addition of Keytruda to chemotherapy resulted in a statistically significant and clinically meaningful improvement in both progression-free survival and overall survival compared to chemotherapy alone as a first-line treatment for patients with metastatic TNBC with a PD-L1 CPS of 10 or more. However, no statistically significant benefit in progression-free survival or overall survival was previously observed in a subgroup of patients with PD-L1 CPS of 1 or higher, and the benefit of the regimen was not tested in the intent-to-treat (ITT) population due to the prespecified testing strategy.

In the trial, investigators enrolled patients 18 years or older with central determination of TNBC and PD-L1 expression. Moreover, patients had to have previously untreated, locally recurrent, inoperable or metastatic disease; de novo metastasis or completion of treatment with curative intent within six months of first disease recurrence; and an ECOG performance status — which measures how much the disease impacts or limits daily living — of 0 or 1. Patients’ life expectancy had to exceed 12 weeks, and adequate organ function was required.

Those with active central nervous system metastasis, active autoimmune disease or who had been previously treated with systemic steroids were not eligible for enrollment.

Patients were randomized to receive either intravenous (IV) Keytruda plus chemotherapy (two-thirds of the population) or placebo plus chemotherapy (one-third of the population). Keytruda was administered at a dose of 200 milligrams (mg) every three weeks. Chemotherapy regimens included:

Furthermore, patients were stratified by chemotherapy regimen (taxane vs gemcitabine/carboplatin), PD-L1 tumor expression (CPS of 1 or greater vs CPS less than 1), and prior treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes vs no).

The main goals of the study were to assess progression-free survival and overall survival in the PD-L1 CPS of 10 or higher, PD-L1 CPS of 1 or higher, and in the ITT populations. Secondary endpoints included objective response rate, duration of response, disease control rate and safety in all treated patients.

In this analysis, researchers sought to assess outcomes in subgroups of patients by additional CPS cut-offs.

Of the 847 total patients enrolled on the study, 566 were randomized to the Keytruda group compared with 281 who were randomized to the placebo group.

A total of 219 patients treated with Keytruda had a PD-L1 CPS of 10 or higher; 421 were treated and had a PD-L1 CPS of 1 or higher; and 562 were treated in the ITT population. Twenty-seven patients with a PD-L1 CPS of 10 or higher completed treatment while 189 discontinued, 35 patients with a PD-L1 CPS of 1 or higher completed treatment and 379 discontinued, and 39 patients in the ITT population completed treatment and 514 discontinued.

Among the 281 patients randomized to placebo, 103 were treated with a PD-L1 CPS of 10 or higher, 211 were treated with a PD-L1 CPS of 1 or higher, and 281 were treated in the ITT population. Five patients with a PD-L1 CPS of 10 or higher completed treatment and 95 discontinued, eight patients with a PD-L1 CPS of 1 or higher completed treatment and 200 discontinued, and 12 patients in the ITT population completed treatment and 264 discontinued.

Baseline characteristics between the two treatment groups were well balanced. The median age was 53 years (range, 22 to 85), and 41% and 38.4% of patients adminstered Keytruda and placebo, respectively, had an ECOG performance status of 1, meaning that they were restricted in strenuous physical activity, but were still able to carry out light and sedentary tasks, such as housework and office work. Additionally, 75.1% of patients in each group had a PD-L1 CPS of 1 or more; 38.9% and 36.7% of Keytruda- and placebo-treated patients, respectively, had a CPS of 10 or higher.

Furthermore, more than half of patients in each group received gemcitabine/carboplatin at 54.9% vs 54.8%, respectively.

Additional data showed that, at a median follow-up of 44 months with Keytruda, the median overall survival among the PD-L1 CPS of 1 or higher group was 17.6 months with Keytruda vs 16 months with placebo, and 17.2 months vs 15.5 months, respectively, in the ITT population. The 18-month progression-free survival rates with Keytruda in the PD-L1 CPS of 1 or higher and ITT groups were 48.4% and 47.8%, respectively; in the placebo groups, these rates were 41.4% and 41.8%, respectively.

Further analyses showed that the median overall survival for Keytruda vs placebo was 16.2 months vs 14.7 months, respectively, in those with a PD-L1 CPS of less than 1; 13.9 months vs 15.5 months, respectively, in those with a CPS of 1 to 9; 20.3 months vs 17.6 months, respectively, in those with a CPS of 10 to 19; and 24.0 months vs 15.6 months, respectively in those with a CPS of 20 or higher.

At a data cutoff date of June 15, 2021, the median progression-free survival among those with a PD-L1 CPS of 1 or higher was 7.6 months in the Keytruda group vs 5.6 months in the placebo group; the one-year progression-free survival rates were 31.7% and 19.4%, respectively. In the ITT population, the median progression-free survival was 7.5 months vs 5.6 months, respectively, and the one-year PFS rates were 29.3% and 20.8%, respectively.

When broken down further, the average progression-free survival for Keytruda vs placebo was 6.3 months vs 6.2 months, respectively, in those with a PD-L1 CPS of less than 1; 5.7 months vs 5.6 months, respectively, in those with a CPS of 1 to 9; 9.9 months vs 7.6 months, respectively, in patients with a CPS between 10 and 19; and 9.2 months vs 5.4 months, respectively in those with a CPS of 20 or higher.

In terms of safety, 96.3% of patients receiving Keytruda vs 95% of patients administered placebo reported treatment-related side effects of any severity; 68.1% vs 66.9%, respectively, had side effects reported as severe, life-threating or fatal. Serious side effects occurred in 17.8% of patients receiving Keytruda vs 12.1% of those administered placebo, and 18.3% vs 11% of patients, respectively, experienced a side effects that led to discontinuation of either study drug. Moreover, 0.4% of patients in the Keytruda group experienced a side effect that led to death.

The most common side effects reported in the Keytruda and placebo groups were anemia (49.1% vs 45.9%, respectively), neutropenia (41.1% vs 38.1%) and nausea (39.3% vs 41.3%).

Keytruda works by activating the patient’s immune system to find and fight cancer, which could lead to immune-mediated side effects. Immune-mediated side effects were reported in 26.5% of patients in the Keytruda group vs 6.4% of those receiving placebo. Additionally, 5.3% of patients in the Keytruda group experienced an immune-mediated side effect that was severe, life-threatening or fatal, 3.4% reported serious immune-related side effects, and 2.8% had an immune-mediated side effect that led to treatment discontinuation; these rates were 0% in the placebo group.

This article was originally published on OncLive as, “

Pembrolizumab Plus Chemotherapy Represents New Standard of Care for Metastatic TNBC With PD-L1 CPS ≥10

For more news on cancer updates, research and education, don’t forget to 

Articles

The combination of Keytruda and chemotherapy improved survival rates in patients with PD-L1—positive metastatic triple-negative breast cancer.

Study Results Champion Keytruda/Chemo as ‘New Standard of Care’ in TNBC Subset

Most patients with large B-cell lymphoma reported positive outcomes and maintenance or improvements in health-related quality of life after receiving second-line Breyzani (liso-cel; lisocabtagene maraleucel), according to findings from the phase 3 TRANSFORM trial.

An analysis of the study presented at the 2021 ASH Annual Meeting, showed that treatment with Breyzani — a CAR-T cell therapy — induced more favorable changes from baseline to day 126 than the standard of care in most of the 30 items found in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Higher scores on the questionnaire represent higher functioning and quality of life.

Specifically, the difference between treatments in terms of cognitive functioning was 2.21 for those treated with Breyzani vs -2.09 with standard of care; the average difference between the treatments for physical functioning was -2.75 and -2.17, respectively. The difference in score between each group was deemed to be statistically significant. Moreover cognitive functioning and physical functioning in the standard of care group tended to deteriorate over time, as the CAR-T cell therapy group was noted to improve.

The individual-level analyses showed that a higher proportion of patients in the Breyzani group improved when it came to fatigue and global health/quality of life (GH/QOL) compared with standard of care. Similarly, a smaller percentage of patients on Breyzani deteriorated than the standard of care group.

Notably, a higher proportion of patients in the standard of care group experienced worsened fatigue (71%) vs. the Breyzani group (18%), and a lower proportion experienced improvement in fatigue, at 29% and 47%, respectively.

A higher proportion of patients in the standard of care group experienced worsened GH/QOL vs. the CAR-T cell therapy group, at 57% and 18%, respectively; moreover, a lower proportion of patients had improved GH/QOL, at 14% and 53%, in the standard of care and Breyzani groups, respectively.

Regarding the other main goals, the proportions of patients with improvement or deterioration favored Breyzani or proved to be similar between the treatment groups.

“Compared with standard of care, liso-cel (Breyzani) showed favorable improvement in most primary (patient reported outcome) domains, particularly EORTC QLQ-C30 cognitive functioning and fatigue and more patients showed (patient reported outcome) improvements and fewer showed deterioration by month six with liso-cel,” lead study author Dr. Jeremy S. Abramson, of the Lymphoma Program at Massachusetts General Hospital Cancer Center in Boston, and colleagues, wrote in the abstract on the data.

Not only did it improve quality of life, but Breyzani’s cancer-fighting abilities were also examined in the TRANSFORM study. The CAR-T cell therapy demonstrated a meaningful improvement in the event-free survival (time after primary treatment ends that a patient remains free of certain complications the treatment was intended to prevent or delay) in this patient population, with no new safety signals observed.

TRANSFORM enrolled patients who were aged 75 years or younger who had relapsed or refractory large B-cell lymphoma and had completed their first-line therapy within 12 months of enrollment. To be eligible for enrollment, patients needed to have been candidates for autologous stem cell transplantation (ASCT).

Study participants were randomized to receive either standard of care, which consisted of three cycles of salvage chemotherapy and carmustine, etoposide, cytarabine and melphalan, plus ASCT for responding patients, or Breyzani following lymphodepletion (a short course of chemotherapy given before CAR-T cell therapy to kill T cells). Notably, patients assigned to the standard of care group were permitted to crossover to receive lymphodepletion if they experienced disease progression.

The EORTC QLQ-C30 and Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) (another quality of life assessment) were administered to patients at the time of randomization, as well as on day 29 (infusion of Breyzani or two cycles of salvage chemotherapy), day 64 (one month post Breyzani or completion of chemotherapy), and day 126 (three months after Breyzani or two months after ASCT), at six months, and other prespecified time points up to 36 months following treatment. No patient-reported outcomes were collected for those who crossed over from standard of care to Breyzani.

The analysis was based on the patient-reported outcome-evaluable population, or those who completed an assessment at baseline, as well as at least one post-baseline assessment, and predefined thresholds determined clinically meaningful changes.

Primary areas of interest included GH/QOL, physical functioning, cognitive functioning, fatigue, pain, and FACT-LymS, and an analysis performed to assess the between-treatment difference in changes from baseline for each group. Furthermore, proportions of patients with meaningful change from baseline were assessed for each primary domain up to six months.

Additional data showed that the overall average change in fatigue was -1.95 in the Breyzani group vs 3.75 in the standard of care group, and the overall average change in pain was -11.14 vs -15.56, respectively.

Additionally, the average score change in GH/QOL was 3.08 in the Breyzani group vs 0.04 in the standard of care group. The overall average change in the FACT-LymS was 1.48 in the Breyzani group vs. 1.63 in the standard of care group.

A version of this article was originally published on OncLive as “

Liso-cel Improves HRQoL Over Standard of Care in Relapsed/Refractory LBCL

Patients with large B-cell lymphoma tended to have better quality of life that continued to improve over time after receiving Breyzani compared to those given standard of care.

CAR-T Cell Therapy Bests Standard of Care in Health-Related Quality of Life for Patients With Lymphoma

Patients whose non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) does not respond to the popular therapy Bacille Calmette-Guérin (BCG) may eventually have more luck by adding the novel drug N-803 (ALT-803), according to findings from a group of patients enrolled in the phase 2/3 QUILT-3.032 clinical trial.

The study met its main goal, with a complete response (CR) rate – meaning that there was no detectable amount of disease – of 72%, and a 58.6% probability of maintaining a CR for at least 12 months. Additionally, at an average follow-up of 20.4 months, the median duration of CR was 19.9 months.

“Eighty-five percent of our patients avoided a cystectomy,” said lead study author Dr. Karim Chamie, associate professor of urology at the University of California, Los Angeles. “This intravesical administration is quite favorable, and quite familiar amongst those who normally treat patients with BCG-unresponsive bladder cancer.”

QUILT-3.032 enrolled 81 patients with histologically confirmed BCG-unresponsive NMIBC, with persistent or recurrent CIS within 12 months of receiving adequate BGC treatment. Patients were treated with 50 mg of BCG plus 400 mg of intravesical N-803 weekly for six weeks, followed by re-induction and maintenance for up to three years.

The primary endpoint (main goal) was biopsy-confirmed CR at three and six months. Secondary end points included duration of CR, cystectomy avoidance and time to cystectomy. Furthermore, safety end points included incidence of serious side effects and immune-related side effects.

Notably, the analysis included patients who achieved a CR at 3 months, as well as those who achieved a CR after rescue and re-induction at 6 months.

Those who were enrolled were heavily pretreated patients with an average of five transurethral (performed through the urethra) resections of a bladder tumor, and a median of 12 prior BCG instillations. Additionally, 42% of patients had received prior treatment with chemotherapy, and 17% were previously treated with immunotherapy agents.

Additional data showed that among patients who achieved an initial complete response at three months, there was a 64% probability of maintaining that response at 12 months, and a 61% probability of maintaining it at 18 months.

Notably, as of May 2021, the combination showed a 30% durable response at 18 months. Eighty-five percent of patients have not progressed to radical cystectomy through a data analysis as of this time point, as well.

In terms of safety, the combination was well tolerated, with no incidence of treatment-related serious side effects, immune-related side effects or treatment-related side effects that were grade 4/5 (life-threatening to fatal) in severity. Severe side effects caused by treatment occurred in just two patients and included urinary tract infection and arthralgia. The most frequent grade mild side effects were painful urination (22%), blood in urine (16%) and frequent urination (19%).

In comparison to other FDA-approved treatments for this patient population, N-803 plus BCG significantly improved outcomes. Previous data with Keytruda (pembrolizumab) showed that the agent induced at CR rate of 41% at any time, and a median duration of CR of 16.2 months at 24.1 months follow-up. Similarly, valrubicin elicited an 18% CR rate, and a median duration of CR of less than six months. Moreover, the cystectomy-free rate for the two drugs was 63% and 76%, respectively.

A version of this article was originally published on OncLive as, “

N-803/BCG Combo Shows Promising Responses, Tolerability in BCG-Unresponsive Bladder Cancer

The novel drug N-803 boosted response to Bacille Calmette-Guérin therapy in patients with non-muscle invasive bladder cancer, a study showed.

New Agent Can Improve BCG Response, Quality of Life in Bladder Cancer

Patients with B-cell malignancies responded well to treatment with the covalent BTK inhibitor TG-1701 at all dose levels in patients.

Updated results from this phase 1/2 trial were presented virtually during the 2021 ASCO Annual Meeting.

While patients with chronic lymphocytic leukemia and other B-cell malignancies have benefitted from treatment with BTK inhibitor monotherapies, complete responses and deep remissions remain rare. TG-1701 is a covalently bound BTK inhibitor that has demonstrated superior selectivity vs other agents, such as Imbruvica (ibrutinib).

In the dose-escalation trial, which included disease-specific groups of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenström macroglobulinemia, the primary objective was to examine the safety and efficacy of TG-1701 alone and in combination with ublituximab/Ukoniq (umbralisib). Additionally, investigators sought to establish the recommended phase 2 dose for the monotherapy and combination regimen.

The trial enrolled patients who were relapsed or refractory to prior standard treatment and had histologically confirmed chronic lymphocytic leukemia or B-cell lymphoma warranting systemic treatment.

The dose-escalation portion of the trial included a TG-1701 monotherapy group and a TG-1701 plus ublituximab/Ukoniq combination group. After the optimal dose had been determined, the trial then moved on to focus on the disease-specific groups, which examined both the single-agent and combination regimens.

Oral TG-1701 was continuously administered daily in 28-day cycles. In the combination groups, an escalating dose of TG-1701 was administered daily, plus an oral dose of Ukoniq at 800 milligrams or 600 milligrams daily and an intravenous dose of ublituximab at 900 milligrams on specific days and cycles.

In the dose-escalation monotherapy group, patients received TG-1701 at 100 milligrams daily, 200 milligrams daily, 300 milligrams daily and 400 milligrams daily.

In the dose-escalation combination group, patients received TG-1701 at 100 milligrams daily and 200 milligrams daily plus ublituximab/Ukoniq. Additionally, patients in the group who received TG-1701 at 300 milligrams daily also received Ukoniq at the 600 milligrams daily dose plus ublituximab at the designated trial dose.

Among the patients who enrolled on the study, the median age was 68 and 69 in the single-agent and combination groups, respectively. Approximately half the total population was men and patients received a median of one prior line of therapy in the single-agent group and two in the combination group.

Of the 125 total patients enrolled on the study, 97 are still receiving ongoing treatment across all groups.

The maximum-tolerated dose of the BTK inhibitor was not achieved in patients who received TG-1701 monotherapy up to a dose of 400 milligrams daily. The efficacy dose-escalation group, which administered 100 milligrams to 400 milligrams of single-agent TG-1701 daily, reported an overall response rate (patients with a partial or complete response to treatment) of 57% after a median follow up of 20.3 months, while the disease-specific monotherapy group, which administered a 200-milligram dose of the agent, yielded an overall response rate of 95% after a median follow up of 12.2 months in patients with chronic lymphocytic leukemia, 65% in patients with mantle cell lymphoma and 95% in patients with Waldenström macroglobulinemia.

In the chronic lymphocytic leukemia group, a single-agent 300-milligram dose yielded an overall response rate of 100% at a median follow up of 8.6 months. Additionally, a dose-escalation group that combined 100 milligrams to 300 milligrams of TG-1701 with ublituximab and Ukoniq daily achieved an overall response rate of 79% at a median follow up of 15.6 months across multiple B-cell malignancies, with a complete response rate of 21%.

“The combination TG-1701 with ublituximab/(Ukoniq) has been well-tolerated and dose escalation continues,” lead study author Dr. Chan Cheah, a clinical professor at the University of Western Australia Medical School, said during an oral presentation on the data. “The combination regimen is associated with encouraging clinical activity, including early complete responses. This study continues enrollment and future registration trials are being planned.”

Across most study groups, the most common reason for treatment discontinuation was disease progression. Notably, two patients discontinued due to non-treatment related side effects in the 200-milligram disease-specific group.

In terms of safety, the most common side effects were mild to moderate in severity and few severe or worse events were reported. In the dose-escalation monotherapy group, the most common any-grade side effects were respiratory tract infection (36%), constipation (32%) and bruising (28%), with common any-grade hematologic and lab abnormalities including neutropenia (low levels of a type of white blood cell called neutrophils; 24%), alanine aminotransferase increase (indication of liver damage; 24%) and aspartate aminotransferase (AST) increase (20%). The most common any-grade side effects in both the disease-specific and chronic lymphocytic leukemia monotherapy groups were respiratory tract infection (10% for each). Common any-grade hematologic and lab abnormalities included neutropenia (13%), anemia (11%) and AKT increase (8%) in the disease-specific group. In the chronic lymphocytic leukemia group, this included alanine aminotransferase increase (15%), aspartate aminotransferase increase (indication of injury mainly to the liver or muscles; 15%) and neutropenia (10%).

Severe or worse side effects included respiratory tract infection (8%) and rash (4%) in the dose-escalation group and COVID-19 (2% and 10%) in the disease-specific and chronic lymphocytic leukemia groups, respectively. In terms of hematologic and lab abnormalities, the most common severe or worse side effects included alanine aminotransferase increase (12%) in the dose escalation group and neutropenia (8% and 10%) in the disease-specific groups and chronic lymphocytic leukemia groups, respectively.

In the combination therapy group, the most common any-grade side effects were diarrhea (47%), chest tightness/facial flushing (47%), bruising (47%), nausea (32%) and high blood pressure (32%). Severe side effects included diarrhea (11%), chest tightness and flushing (5%), high blood pressure (5%) and nausea (5%). Moreover, 11% and 5% of patients experienced life-threatening neutropenia and alanine aminotransferase increase, respectively.

“In terms of laboratory abnormalities, neutropenia was the most common (severe) or higher (side effect), seen in 8% of patients all together,” Cheah said.

Investigators concluded that these findings provide the rationale for further daily dosing with TG-1701.

TG-1701 monotherapy or added to ublituximab and Ukoniq contributed to early complete responses in patients with B-cell malignancies.

Courtney Marabella

Study Results Champion Keytruda/Chemo as ‘New Standard of Care’ in TNBC Subset

CAR-T Cell Therapy Bests Standard of Care in Health-Related Quality of Life for Patients With Lymphoma

New Agent Can Improve BCG Response, Quality of Life in Bladder Cancer

Novel BTK Inhibitor Well Tolerated in Patients with CLL, Other B-Cell Malignancies

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