Conor Killmurray

Patients with B-cell malignancies who were intolerant to prior treatment with Calquence (acalabrutinib) experienced clinically meaningful benefits with Brukinsa (zanubrutinib).

Patients with B-cell malignancies who were intolerant to prior treatment with Calquence (acalabrutinib) experienced clinically meaningful benefits with Brukinsa (zanubrutinib), showing the viability of Brukinsa in this patient population, according to data presented at the 2023 

Results from the ongoing phase 2 BGB-3111-215 study showed data from a cohort of 27 patients intolerant to Calquence. The median exposure to Brukinsa lasted six months longer than the patient’s cumulative exposure to Calquence before treatment discontinuation at 11.4 months versus 5.4 months, respectively.

Further, 70% of the Calquence intolerance side effects experienced by patients did not reoccur at any grade with Brukinsa. Of those that did recur, no events recurred at a higher severity. The most common grade 2 or higher Calquence intolerance side effects that recurred during treatment with Brukinsa included arthralgia (joint pain, six events), headache (five events), myalgia (muscle pain, five events), diarrhea (three events), rash (three events), fatigue (two events) and hemorrhage (two events).

According to Dr. Mazyar Shadman, who presented these data at the 2023 ASH meeting, no side effects led to death, but two side effects led to treatment discontinuation of Brukinsa. Other patients discontinued Brukinsa due to physician decision (two patients), patient withdrawal (two patients) and progressive disease (PD; one patient). The side effects that led to discontinuation of Brukinsa were a recurrence of grade 2 myalgia in one patient and grade 3 diarrhea in another.

Looking at grade 3 or higher side effects, three patients experienced a neutrophil count decrease after Brukinsa, but anemia, thrombocytopenia, nor platelet count decrease occurred. Overall, seven patients had a serious side effect with 16 of those leading to dose interruption and six leading to dose reduction.

In the phase 2 study, patients with previously treated B-cell malignances included those with chronic lymphocytic leukemia (CLL; 17 patients), small lymphocytic lymphoma (SLL; two patients), Waldenström’s macroglobulinemia (four patients), mantle cell lymphoma (two patients) or marginal zone lymphoma (two patients). To be enrolled in the study, they had to be deemed intolerant of a prior Bruton tyrosine kinase (BTK) inhibitor treatment and could not have either Richter transformation or PD while on BTK treatment. In the first cohort of the study, 57 patients intolerant to Imbruvica (ibrutinib) were enrolled. In cohort 1 and 2, patients were given either 160 mg of Brukinsa twice a day or 320 mg once a day.

The median age of patients in cohort 2 was 73, with a majority of male patients (63%); most had an ECOG performance status of 0 (67%), meaning they could perform daily tasks with no assistance.

According to Shadman, associate professor in the clinical research division and innovators Network Endowed Chair at the Fred Hutch Cancer Center, previous findings from the first cohort showed similar promise with Brukinsa after ibrutinib. In cohort 2, 19 of the Calquence-intolerant patients received the 160 mg dose and 8 received the 320 mg dose. Thirteen of the 27 patients intolerant to Calquence were also intolerant to previous use of ibrutinib, with 12 given a prior ibrutinib monotherapy and 1 patient on an ibrutinib combination therapy.Twenty-six patients intolerant to Calquence received the BTK as a monotherapy and one patient was intolerant to an Calquence combination regimen.

Twenty-five of the patients in cohort 2 were evaluable for efficacy after Brukinsa treatment. Investigators observed a 96% disease control rate, defined as patients with stable disease (SD) or better with Brukinsa. There was an overall response rate of 64%, defined as having a minor response or better, to the next-generation BTK inhibitor.

Overall, 48% of patients had a partial response, 4% had a very good partial response, 4% had a minor response, 32% had SD and 4% had progressive disease. The median time to best overall response was three months and time to the first overall response was seen at a median of 2.9 months. Of the patients with either CLL or SLL, 71% had a partial response with lymphocytosis or better.

“The results of this study demonstrated that (Brukinsa) may be a viable option for patients who are intolerant of (Calquence),” concluded Shadman.

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Results from an ongoing phase 2 study show the viability for the use of Brukinsa after patients with previously treated B-cell malignancies are deemed intolerant to the next-generation Bruton tyrosine kinase inhibitor Calquence.

Brukinsa Viabie for Calquence-Intolerant B-Cell Malignancies

The use of post-surgical (adjuvant) Libtayo (cemiplimab)in patients with resectable stage 2-4 cutaneous squamous cell carcinoma (CSCC) showed a survival benefit after a year and a half of follow up, leading to a wider phase 3 study, according to data presented at the ESMO 2023 Congress.

Data included one-year follow up of a single-arm, multicenter phase 2 study that looked at the use of Libtayo therapy after surgery. A year ago, researchers published data for 79 patients given neoadjuvant (presurgical) Libtayo prior to surgery, which showed the first part of the study met its primary endpoint with 40 patients achieving a pathological complete response (pCR; no residual invasive disease in the breast and lymph nodes) and 10 patients who achieved a major pathological response (MPR; less than or equal to 10% residual viable tumor).

Now, researchers found that after a year and a half of follow up after surgery and adjuvant therapy, all 40 patients who achieved a pCR did not have disease recurrence, while just one patient who had an MPR recurred.

“It's important to note that in the adjuvant portion of the trial, it was left to investigator discretion whether patients would receive adjuvant Libtayo up to 48 weeks, adjuvant radiation, or observation, and this was based on local pathology review,” explained Dr. Neil D. Gross, professor, and director of clinical research in the department of head and neck surgery at The University of Texas MD Anderson Cancer Center in Houston, who presented these data at the meeting in Madrid, Spain.

Among the patients who initially achieved a pCR, only one patient was given adjuvant radiation therapy. And this group of patients had an estimated 12-month event free survival (EFS, the measure of time after treatment that a group of people in a clinical trial has not had cancer come back or get worse) rate of 94.9%

compared with 72.0% in the 22 patients who did not have surgery or were non-responders. Further, the 12-month EFS rate was also superior in the MPR (10 patients) and pathological partial response (pPR; seven patients) groups compared with those who didn’t respond at 89% and 100%, respectively.

Among all patients given neoadjuvant Libtayo, the median EFS was not reached, but the estimated 12-month EFS rate was 89%. Median EFS was also not reached in the pCR, MPR and pPR groups who had adjuvant therapy compared with a median EFS of 25 months in the non-responder group.

These data were also published concurrently in The Lancet Oncology, where a post-hoc sensitivity analysis was done for 74 patients with stage 3-4 disease. In this group, their 12-month estimated EFS rate was 88% and 87% at 24 months.

At a median follow-up of 18.7 months (range, 1.3-30.4 months), researchers also found a 12-month overall survival (OS) rate of 92%, but median OS was not reached. Further, among the 70 patients that underwent surgery, six patients (9%) had disease-free survival.

“What is shown here is the stark contrast between patients who had any pathologic response and those who either did not have surgery or did not have a pathologic response in favor of the responders,” explained Gross.

Of the 79 patients enrolled, 70 had surgery with 65 patients having post-surgical management data. Overall, 49% were observed after surgery, 25% were given adjuvant Libtayo and 26% had adjuvant radiotherapy. Researchers conducting part 1 of this study administered Libtayo at 350 mg every three weeks for four doses before patients underwent surgery. At the time, an objective response was seen in 68%. In this first part of the study, 87% of patients had a side effectof any grade that occurred during the study with 18% of patients experiencing grade 3 or higher side effect.

Now, among all patients, 89% had a treatment-emergent side effect of any grade and 19% had a grade 3 or greater treatment-emergent side effect. One death was attributed to study treatment for a 93-year-old patient with congestive heart failure exacerbation, which was previously reported. In the adjuvant Libtayo group, no new safety signals were observed with a treatment-emergent side effects of any grade experienced by 10% or more of patients seen in 13 patients and four patients had a grade 3 or greater a treatment-emergent side effect. The most common a treatment-emergent side effect of any grade were diarrhea

(25%), fatigue (25%), increased blood creatinine (25%) and squamous cell carcinoma of the skin (25%).

The four grade 3 or greater a treatment-emergent side effects included one patient with cardiomyopathy, one patient with hypophysitis, one patient that underwent a limb amputation and one patient with increased blood potassium. The cases of grade 3 worsening cardiomyopathy and hypophysitis were considered serious a treatment-emergent side effects; however, no deaths were related to Libtayo.

“These data support the development of a randomized phase 3 trial, which is underway and set to begin enrollment in 2024,” concluded Gross. 

A recent phase 2 study showed promising survival improvements with neoadjuvant Libtayo in patients with cutaneous squamous cell carcinoma after a year and a half follow up.

Libtayo Shows Survival Benefit In CSCC After Year Follow Up

Front-line Imfinzi (durvalumab) plus tremelimumab elicited better overall survival outcomes than standard-of-care chemotherapy for patients with metastatic non-small cell lung cancer, according to findings from a group of patients enrolled on the phase 3 NEPTUNE clinical trial that were presented at the 2022 World Conference on Lung Cancer.

Outcomes tended to vary based on expression levels of PD-L1, a protein that helps hide cancer cells from the immune system.

In particular, overall survival (time from treatment until death of any cause) was more favorable in the 55 patients with low PD-L1 status, defined as PD-L1 expression less than 1%, as well as the 160 patients in the intent-to-treat population — which is all of the patients who were involved in the study — who were treated with the frontline combination.

Overall Survival Favors Imfinzi Plus Tremelimumab

The 26 patients with PD-L1 expression less than 1% treated with the combination demonstrated a median overall survival of 15 months, compared to 11.7 months in the 29 patients treated with chemotherapy, reducing the risk for death by 40%.

This favorable overall survival trend for Imfinzi plus tremelimumab over chemotherapy was consistent across multiple time points. At 12 months, 68% of patients on the combination were alive, compared to 46.4% in the chemotherapy group. At 18 months, 44% and 39.3% of patients were alive in the combination and chemotherapy groups, respectively, and at 24 months, survival rates were 36% and 17.9%, in each group, respectively.

In the entire study population, 78 patients received the two-drug combination. Their average overall survival was 20 months — an improvement over the 82 patients who received chemotherapy and had an overall survival average of 14.1 months. Similarly, 12-, 18- and 24-month overall survival rates were superior with Imfinzi plus tremelimumab over chemotherapy at 72.8% versus 53.1%, respectively, 54.6% versus 41.8%, and 44.2% versus 30.4%.

In secondary analyses, patients with PD-L1 at or above 25% treated with Imfinzi plus tremelimumab (six patients) showed a median overall survival of 36.6 months, compared with 15.8 months in those treated with chemotherapy (four patients), reducing the risk for death by 44%. The overall survival rates also favored the combination arm in the 12-, 18- and 24-month marks at 80.6% versus 56.3% respectively; 64.5% versus 46.3%; and 54.8% versus 36.4%, in the combination group versus the chemotherapy group, respectively.

Similarly, patients with PD-L1 at or above 50% treated with the combination regimen (25 patients) demonstrated a median overall survival of 36.6 months, compared to 15.8 months with chemotherapy (28 patients), reducing the risk for death by 53%. Twelve-, 18- and 24-month overall survival rates were 84% versus 57.1%; 68% versus 45.7%; and 60% versus 34.3%, in the combination group and chemotherapy group, respectively.

Drug Combo Does Not Prolong Time to Progression

Although overall survival continually favored Imfinzi plus tremelimumab, progression-free survival, which is the time from treatment until the disease progresses or worsens, was similar between the two treatments in the primary analysis, overall study population and all PD-L1 subgroups.

In the low PD-L1 status group, median progression-free survival in the Imfinzi plus tremelimumab group was 5.1 months compared with six months. Moreover, the progression-free survival rate at 12 months was just slightly higher in the combination group at 15.6% compared with 11.3% for patients on chemotherapy.

The whole study population exhibited similar results, with a median progression-free survival of 4.2 months compared to six months in the combination and chemotherapy groups, respectively. The 12-month progression-free survival rate was higher, but not significantly, in the Imfinzi plus tremelimumab group (23.9%) compared with chemotherapy (16%).

Similarly, those with PD-L1 at or above 25% and PD-L1 at or above 50% treated with the combination regimen demonstrated a median progression-free survival of 6.8 months and 6.8 months, respectively, compared with 5.7 months and 5.7 months with chemotherapy.

Objective Response and Duration of Response

According to the researchers, response to Imfinzi plus tremelimumab depended on their PD-L1 expression. Patients on the combination therapy showed an objective response rate, which measures how much a tumor shrinks as a result of treatment, of 23.1% compared with 41.4% in patients on chemotherapy.

In the overall population, objective response rate was 35.9% in the Imfinzi plus tremelimumab group, compared to 39% in the chemotherapy arm.

Duration of response was also higher with the combination in the low PD-L1 group at 10.5 months compared with 6.1 months with chemotherapy. Median duration of response in the entire population was also higher for patients on Imfinzi plus tremelimumab at 12.9 months, compared to 6.1 months for those on chemotherapy.

More patients experienced ongoing responses at 18 months with Imfinzi plus tremelimumab in both the intent-to-treat population (46.4% versus 7.6%) and low PD-L1 expression group (33.3% versus 13.6%). According to the researchers, these results were similar in the PD-L1 50% or higher subgroup; however, these data were not shown in the poster presentation.

Lastly, Imfinzi plus tremelimumab was well tolerated with no new safety signals. In the overall population, the rate of grade 3 or 4 treatment-related side effects was lower in the Imfinzi plus tremelimumab group, compared to the chemotherapy group, at 31.2% and 52.6%, respectively.

Imfinzi Plus Tremelimumab Has a Better Side Effect Profile

The most common grade 3 or 4 side effects (serious or severe) with Imfinzi plus tremelimumab in the overall population were increased amylase, which could cause pancreas issues (9.1%), increased lipase, which could also indicate liver disease (9.1%), increased GGT, a sign of liver damage (3.9%) and diluted levels of sodium in the body (3.9%).

Six patients treated with the combination therapy had to discontinue treatment due to side effects, compared with 10 patients who received chemotherapy, including three patients who discontinued treatment due to a side effect in the combination arm. Twenty patients treated with the combination regimen experienced any immune-mediated side effect.

Median age was 62 years. Median duration of treatment at the time of data cut off was 24.9 weeks in the combination group compared with 18.9 weeks in the chemotherapy group. The majority of patients were former smokers or current smokers. Brain and liver metastases were present in 23 and 24 patients, respectively, in the overall population, and nine and 10 patients, respectively, in the low PD-L1 group.

“Our findings suggest that, among Chinese patients with metastatic NSCLC, those with low PD-L1 levels and also those in the whole cohort, treatment with Imfinzi plus tremelimumab may provide a better chance of living longer than treatment with chemotherapy,” the researchers concluded.

Imfinzi plus tremelimumab led to better overall survival outcomes compared to standard chemotherapy in patients with metastatic non-small cell lung cancer. 

Two-Drug Combo Bests Chemotherapy in Front-Line Lung Cancer Treatment

Pre-surgical treatment interruptions can negatively impact early-stage breast cancer outcomes, and a recent study presented at the 

 (SABCS) found that Black patients experience these therapy changes more often than their White counterparts.

“While common, treatment modification or discontinuation has the potential to impair responses,” the researchers wrote in their poster presentation. “We found that African American patients were more likely to have treatment modifications in this cohort, which may contribute to poorer outcomes in this patient population.”

Researchers conducted a retrospective review of 173 patients who had received neoadjuvant (pre-surgical) therapy from January 2010 through March 2020 and separated the patients into two cohorts: a group of 114 patients who received a scheduled regimen (SR); and another group of 59 patients who received a modified regimen (MR).

Although there were nearly double the number of patients in the SR group than in the MR group, Black patients accounted for 59% of the MR cohort.

In the MR group, a significantly lower proportion of patients achieved a pathologic complete response — meaning that there were no detectable signs of cancer — compared with the SR group. Moreover, similar to previous study findings, 42% of Black patients had treatment interruptions compared with 25% of White patients.

“During neoadjuvant therapy in breast cancer, treatment interruptions may impact rates of pathologic complete response and ultimately increase risk of recurrence,” the study authors wrote in their poster.

Six patients (10%) had early discontinuation of doxorubicin and cyclophosphamide; 25 patients (42%) had an early discontinuation of a taxane therapy; seven patients (12%) had an anti-HER2 therapy discontinued; and 21 patients (36%) had dose reductions throughout their therapy.

The study authors observed a pathologic complete response rate of 42% in the SR group, compared with less than half that (20%) in the MR group.

The researchers also used a modeling platform called TumorScope to analyze patient data in the MR group and simulate what their responses to treatment may have been if patients had received the full, uninterrupted dose of their treatment.

The simulation demonstrated that without treatment interruption, 10 additional patients (5.6%) in that group would have been able to achieve a pathologic complete response. In the simulation, 100% of patients receiving SR had a complete response in comparison with 81.7% of those who would experience treatment interruptions.

TumorScope was previously evaluated in a separate study to determine its effectiveness and was used in several other studies and analyses presented at this year’s SABCS. According to the researchers of this study, the results show that TumorScope can be used to estimate the impact of variable dosing before clinicians decide to interrupt a patient’s treatment.

Furthermore, researchers believe that TumorScope can evaluate individual treatments being considered for this patient population to support de-escalation of therapy ahead of time but note that further study is needed.

“In this proof-of-concept study, (TumorScope) can be used to estimate the impact of variable dosing on (pathological complete response; allowing clinicians and patients to make better informed decisions on the impact of regimen modifications on response to (neoadjuvant treatment),” the researchers wrote.

Treatment modifications in the pre-surgery setting led to a lower rate of pathologic complete response in Black patients with breast cancer, the researchers found.

Conor Killmurray

Brukinsa Viabie for Calquence-Intolerant B-Cell Malignancies

Libtayo Shows Survival Benefit In CSCC After Year Follow Up

Two-Drug Combo Bests Chemotherapy in Front-Line Lung Cancer Treatment

Black Patients More Likely to Experience Treatment Changes That May Worsen Breast Cancer Outcomes

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