Dylann Cohn-Emery

Patients with high-risk, early-stage triple-negative breast cancer (TNBC) in the phase 3 KEYNOTE-522 trial (NCT03036488) of pembrolizumab (Keytruda) plus chemotherapy after surgery demonstrated statistically significant event-free survival (EFS), according to a press release from Merck.

When compared with pre-operative chemotherapy, an interim analysis by the Data Monitoring Committee revealed that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab monotherapy had a statistically significant and clinically meaningful improvement in EFS. This met one of the dual primary end points of the trial, the other primary end point, pathologic complete response (pCR), was already met.

“Keytruda is the first immunotherapy to show positive results for EFS in patients with high-risk early-stage TNBC, a particularly aggressive form of breast cancer,” Roy Baynes, MD, PhD, senior vice president, head of global clinical development, and chief medical officer of Merck Research Laboratories, said in a statement.

“The improvement in pCR rates initially observed following pre-operative treatment was encouraging, and now that we are seeing the data mature after 4 years to include a statistically significant improvement in EFS, we look forward to working with the FDA and other global authorities to bring this new option to patients as quickly as possible. We are grateful to the study participants who are critical to our efforts to advance potential treatment options for patients with TNBC,” Baynes concluded.

In this 2:1 randomized, double-blind trial, 784 patients received 200 mg of pembrolizumab every 3 weeks combined with paclitaxel and carboplatin for 4 cycles, followed by pembrolizumab plus cyclophosphamide and doxorubicin or epirubicin prior to surgery, then after surgery, pembrolizumab alone every 3 weeks for up to 9 cycles. Placebo was given with chemotherapy in the same design as the pembrolizumab group to 390 patients.

During the European Society for Medical Oncology (ESMO) 2019 meeting and subsequently in the 

, an interim analysis of pCR for these patients were presented and published. There was a statistically significant increase in 

 among the 602 patients evaluated, with a pCR of 64.8% (95% CI, 59.9%-69.5%) versus 51.2% (95% CI, 44.1%-58.3%) in patients receiving placebo. The estimated difference was 13.6 percentage points (95% CI, 5.4-21.8; 

At median follow-up of 15.5 months (range, 2.7-25.0 months) in the published data, 7.4% (n = 58/784) of patients receiving pembrolizumab and chemotherapy versus 11.98% (n = 46/390) of those receiving placebo and chemotherapy had disease progression that died from any cause, had local or distant recurrence or a second primary tumor, or precluded surgery (HR, 0.63; 95% CI, 0.43-0.93).

There were no new safety signals in the analysis of EFS and the safety profile of pembrolizumab remained consistent with previously reported studies.

 In the published data, the incidence of grade 3 or higher treatment-related adverse events was 78.0% and 73.0% in patients given pembrolizumab and placebo, respectively; this included the death in 3 patients in the pembrolizumab arm and 1 patient in the placebo arm.

In a subgroup analysis of KEYNOTE-522, a presentation at the ESMO Asia Virtual Congress 2020 showed that the combination of 

pembrolizumab and chemotherapy significantly increased pCR in Asian patients with TNBC

 Of the 215 Asian patients enrolled, 136 were given the pembrolizumab regimen. At median follow-up of 13.0 months, the pCR rate among the first 125 Asian patients was 59% (95% CI, 47%-70%) in the 75 patients receiving pembrolizumab versus 40% (95% CI, 26%-55%) in those receiving placebo.

After a vote of 10 to 0 by the FDA’s Oncologic Drugs Advisory Committee that a regulatory decision should be deferred until more data came out of KEYNOTE-522, the FDA gave Merck a Complete Response Letter in March 2021 for their supplemental Biologics License Application for the approval of pembrolizumab in patients with high-risk, early-stage TNBC based on the pCR and early interim EFS findings.

Merck announces phase 3 KEYNOTE-522 trial met dual primary endpoint of event-free survival (EFS) in patients with high-risk early-stage triple-negative breast cancer (TNBC). News release. Merck. Published May 13, 2021. Accessed May 13, 2021. 

Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. 

 KEYNOTE-522 Asian subgroup: phase 3 study of neoadjuvant pembrolizumab (pembro) vs placebo (pbo) + chemotherapy (chemo) followed by adjuvant pembro vs pbo for early triple-negative breast cancer (TNBC). Presented at: ESMO Asia Virtual Congress 2020; November 20-22, 2020. Accessed May 13, 2021. 

Articles

Patients with high-risk, early-stage triple-negative breast cancer in the phase 3 KEYNOTE-522 trial of pembrolizumab plus chemotherapy after surgery demonstrated statistically significant event-free survival.

Pembrolizumab Achieves Prespecified Event-Free Survival in High-Risk TNBC

Roughly 4% of patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib (Imbruvica) may experience atrial fibrillation (AF), but their comorbidities, rather than their CLL-related factors, predict risk of treatment-emergent AF, according to a retrospective review published in 

Treatment-emergent AF was associated with shorter event-free survival (EFS) and overall survival (OS) in patients treated with ibrutinib at Mayo Clinic between October 2012 and November 2018, but a majority of patients were able to continue on therapy.

“In this large, retrospective analysis of [patients with] CLL treated with ibrutinib, the risk of treatment-emergent AF at 2 years was ~16%, which is significantly higher than that reported in ibrutinib registration trials,” the authors wrote in their discussion of the review. “As would be expected, comorbidities of patients (particularly past history of AF and heart failure) and not CLL characteristics (such as Rai stage, CLL [fluorescence in situ hybridization] profile or 

 mutation status) predicted the development of treatment-emergent AF.”

Of the 298 patients with CLL identified in the Mayo Clinic CLL Database, 51 developed treatment-emergent AF after receiving ibrutinib. There were 39 incidents of AF and 12 incidents of recurrent AF. Persistent AF was present in 8 (2.7%) patients when they started ibrutinib therapy. Twenty-one of the other 290 had prior history of AF but 9 did not relapse when receiving ibrutinib.

The risk of treatment-emergent AF was 9% at 6 months (95% CI, 6%-13%), 12% at 1 year (95% CI, 9%-17%), and 16% at 2 years (95% CI, 12%-21%). Patients with recurrent AF had a higher estimated cumulative incidence of treatment-emergent AF: 43% (95% CI, 25%-71%) at 1 year, 48% (95% CI, 30%-76%) at 2 years, and 56% (95% CI, 36%-86%) at 3 years. 

= .0028) were both associated with increased risk of treatment-emergent AF in multivariate analyses. After adjusting for age, prior treatment status, 

 disruption, past history of AF, valvular disease, and heart failure, the data showed patients who experienced treatment-emergent AF tended to have shorter OS (HR, 3.2; 

In a univariable analysis, patients who experienced treatment-emergent AF also had shorter EFS (HR, 2.7; 95% CI, 1.6-4.5; 

< .001) and OS (HR, 4.1; 95% CI, 2.3-7.3; 

< .001). The univariable analysis also showed statistically significant risk factors for developing AF were a history of AF (HR, 4.8; 95% CI, 2.5-9.4; 

< .0001), heart failure (HR, 4.8; 95% CI, 2.6-8.9; 

< .0001), valvular heart disease (HR, 3.4; 95% CI, 2.0-5.9; 

< .0001), age of 65 years or older (HR, 2.5; 95% CI, 1.3-5.1; 

< .008), sleep apnea (HR, 2.1; 95% CI, 1.02-4.4; 

< .04), and hypertension (HR, 1.8; 95% CI, 1.003-3.1; 

There were 13 (25%) patients with grade 3 or more treatment-emergent AF. Rate control measures such as beta blockers were used to manage treatment-emergent AF in 27 (53%) patients, 2 (4%) patients received digoxin for rhythm control, and 1 (2%) patient received both. Additional interventions were used in 16 (31%) patients; this included cardioversion in 11 patients, atrioventricular nodal ablation in 3 patients, and placement of a permanent pacemaker in 2 patients. There were 5 (10%) patients who did not receive therapy for their treatment-emergent AF.

Dose reduction of ibrutinib was used in 22 (43%) patients so they could continue on therapy. Twelve (24%) patients had ibrutinib held temporarily at the onset of treatment-emergent AF and then resumed their original dose later. There were 11 patients who continued their ibrutinib dose without interruption or reduction. Lastly, 6 (12%) patients permanently discontinued due to treatment-emergent AF.

For the entire cohort, there was a median EFS of 3.9 years in, and a median OS of 5.3 years. The median age for ibrutinib initiation was 68 years (range, 35-93) and 70.5% were men. Almost 70% were being treated for relapsed/refractory disease, with a median of 1 prior therapy (range, 0-15). There was a median time on ibrutinib of 19 months (range, 0.23-69.7 months).

“The results of our study, obtained from careful follow-up of patients treated at our center, provide important information to practicing clinicians about the prediction, incidence, and management of AF in patients with CLL treated with ibrutinib. Patient comorbidities including history of AF and heart failure predicted risk of treatment-emergent AF in patients treated with ibrutinib. Most patients who develop AF are able to continue ibrutinib therapy, but the occurrence of AF appears to be associated with adverse clinical outcomes,” the authors concluded.

Archibald WJ, Rabe KG, Kabat BF, et al. Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib: risk prediction, management, and clinical outcomes. 

. 2021;100(1):143-155. doi:10.1007/s00277-020-04094-3

Roughly 4% of patients with chronic lymphocytic leukemia treated with ibrutinib may experience atrial fibrillation, but their comorbidities, rather than their CLL-related factors, predict risk of treatment-emergent AF.

Prior Comorbidities Predict Risk of Treatment-Emergent Atrial Fibrillation in CLL

The eligibility for and responses to genome-targeted oncology agents increased in United States among patients with cancer from 2006 to 2020, according to updated estimates published in the Annals of Oncology.

The investigators estimated that there was a 4.31% increase in 

, from 2.73% in 2006 to 7.04% in 2020. In the United States, the percentage of patients with cancer who responded to this type of therapy was modest. Most of the increase in response was observed prior to 2018 and most of the increase in eligibility was observed after 2018.

“Prior studies have evaluated the percentage of patients [in the United States] with advanced or metastatic cancer who are eligible for and respond to this class of medications,” the investigators wrote in their article. “Specifically, genome-targeted therapy was found to apply to 8.3% of patients as of 2018, and 4.9% might experience a partial or complete response. However, since that publication, the number of FDA approvals for drugs targeting genetic indications has grown rapidly. We, therefore, sought to update the estimates of both eligibility for and response to genome-targeted and informed therapies for drugs that have been FDA-approved to reflect estimates as of 2020.”

To calculate the estimates for genome-targeted therapies, the investigators looked at drugs approved for use based on genomic test results where the detected aberration is targeted by the drug. They also looked at and genome-informed therapies, defined as any drug given after a genomic test regardless of if that drug was meant to 

target the abnormalities the patient expressed on the test

The FDA-approved genome-targeted or genome-informed therapies were evaluated by the date they were approved, their indication, tumor type, genomic indication, and response rate. By using mortality data from the American Cancer Society, the investigators estimated the eligibility for these drugs based on prevalence statistics. Eligibility was then multiplied by the response rate in the FDA label to create an estimate for the percentage of patients with cancer in the United States who responded.

Spanning 18 cancer types and 36 genomic indications were 72 different approvals for 51 genome-targeted or genome-informed treatments from 2006 to 2020. The eligibility for genome-targeted therapy was estimated to be 5.13% (95% CI, 5.07%-5.19%) in 2006. By the end of 2018, this increased to 8.82% (95% CI, 8.75%-8.90%). In 2020, it was 13.60% (95% CI, 13.51%-13.68%).

In 2006, there was an estimated eligibility for genome-informed therapy of 10.70% (95% CI, 10.62%-10.78%), which in increased to 16.54% (95% CI, 16.45%-16.63%) in 2018, and then 27.30% (95% CI, 27.19%-27.41%) in 2020.

Response to genome-targeted therapy in 2006 was estimated at 2.73% (95% CI, 2.69%-2.78%). In 2018, it increased to 5.48% (95% CI, 5.43%-5.54%) and then 7.04% (95% CI, 6.98%-7.10%) in 2020. Genome-informed therapy responses were estimated at 3.33% (95% CI, 3.29%-3.38%), 7.68% (95% CI, 7.62%-7.75%), and 11.10% (95% CI, 11.03%-11/19%) in 2006, 2018, and 2020, respectively. All of the response estimations were based on the prevalence of the disease and prevalence of the mutation for the respective cancer type.

In the FDA approval notifications for genome-targeted therapy, the median duration of response was 18.9 months (range, 5.7-80 months) in 2006 and 17.6 months (range, 4.6-80 months) in 2020. There was a median response rate of 19.0% (range, 10.6%-95.3%) and 63.5% (range, 12%-95.3%) in 2006 and 2020, respectively.

“With an increasing number of people who are both eligible for and respond to genomic therapies, it is important to consider access to genomic testing,” the investigators wrote in their discussion. “…In considering which genetic markers should be tested, we need to consider those for which there are available treatment options that have been shown to improve meaningful outcomes such as overall survival and not just those mutations that have tests available for them.”

Haslam A. Kim MS, Prasad V. Updated estimates of eligibility for and response to genome-targeted oncology drugs among US cancer patients, 2006-2020. 

. Published April 12, 2021. Accessed April 22, 2021. 

The eligibility for and responses to genome-targeted oncology agents increased in United States among patients with cancer from 2006 to 2020.

Response to Targeted Therapy Increased From 2006 to 2020 in Patients With Cancer

Chimeric antigen receptor (CAR) T-cell therapy mediates antigen-dependent and
 -independent antitumor effects, and CAR T-cell activation of host antitumor immunity is critical for productive solid tumor CAR T immunotherapy, according to findings from laboratory studies presented by Christine E. Brown, PhD, at the virtual American Association of Cancer Research (AACR) Annual Meeting 2021.

Findings from the analyses show that CAR T-cell may be able to transform the tumor microenvironment to elicit anti-tumor immunity in solid tumors.

Brown, the deputy director of the T cell Therapeutic Research Laboratory at Beckman Research Institute of City of Hope, and her colleagues analyzed the role of the endogenous immune system in productive CAR T-cell responses and if CAR T cells can promote endogenous immunity in mouse models of glioblastoma treated with CAR T-cell therapy. They found that polyclonal immune responses could potentially be generated by productive CAR T cell–mediated induction to address tumor heterogeneity and immunological memory to reduce the potential for tumor relapse.

The investigation of CAR T cells for patients with glioblastoma started after Brown, et al, wrote a case report on a patient with recurrent, multifocal glioblastoma who experienced a complete response after treatment with CAR T therapy. The patient achieved this response despite having target antigen heterogeneity; some parts of the patient’s tumor expressed low or negative levels of interleukin-13 receptor alpha 2 (IL13Rα2), but other parts expressed medium or high levels. The investigators explored the idea of whether there was a chance CAR T cells led to the activation of the patients host immune system, according to Brown.

“Consistent with this notion, we found that after each CAR T-cell infusion, we saw an increase in immune cells into the cerebral spinal fluid. While CAR T cells were detected, the majority of these immune cells were from the host immune system showing endogenous CD3 and CD14 myeloid population,” Brown explained.

In addition to the endogenous immune cells, Brown said there were also spikes of inflammatory cytokines that coincided with each infusion of CAR T cells. The investigators concluded that CAR T cells could potentially change the landscape of glioblastoma and other solid tumors.

This line of investigation inspired Darya Alizadeh, PhD, another investigator on the case report, to look at CAR T therapy and host antitumor immunity in co-culture assays. Alizadeh looked at responses to CAR T-cell therapy before and after patient’s treatment. By isolating CD3 cells in patient’s blood before and after therapy, she observed that T cells isolated after treatment had greater reactivity. This was demonstrated by greater proliferative potential on the autologous tumor, greater interferon gamma (IFNγ) production, and the ability to target and kill the patient’s tumor.

These observations led to Alizadeh and her colleagues creating an immunocompetent mouse model of glioblastoma to further investigate the connection between CAR T cells and the host immune system. They looked at murine IL13Rα2-CAR and a murine CAR T-cell production platform to show they could engineer murine CAR T cells to express the CAR with a balanced CD4 and CD8 ratio, Brown said. The murine CAR T cells demonstrated IL13Rα2-dependent killing and cytokine production.

The investigators looked at several syngeneic murine models, and one that stood out was the KR158, which grows in a highly invasive and aggressive manner, according to Brown. It expresses high myeloid cell infiltrates and a T cell-excluded phenotype; features which the investigators felt were consistent with human clinical glioblastoma.

After choosing the design, the investigators looked at the ability of IL13Rα2-targeted CAR T cells to target glioblastoma in the syngeneic mouse model and demonstrated that a single infusion of these CAR T cells could produce long-term survival in the majority of mice.

To understand the role of endogenous immune system in the antitumor response, the investigators compared activity in immune-competent mice with activity in immune-compromised mice.

“To our surprise, we saw that CAR T cells mediated superior antitumor responses in immune-competent mouse models, suggesting that CAR T cells may stimulate an endogenous T-cell response or antitumor response,” Brown said.

The investigators used cured mice from the immune-competent models and rechallenged them with antigen negative tumors to test this hypothesis. The cured mice exhibited host antitumor immunity and rejected antigen negative tumors after CAR T-cell therapy, which suggested the investigators were inducing new CAR T-cell responses or tumor reactivity.

After seeing these results, the investigators then isolated endogenous T cells from mice with untreated tumors and compared them with endogenous T cells from mice who received CAR T-cell treatment. In vitro co-culture assays showed that endogenous T cells from mice treated with CAR T cells had greater tumor reactivity in a tumor killing assay and T cell proliferation assay.

“This is really important because it suggests that antitumor reactivity by the host immune system isn’t just due to exposure to the tumor itself but really relied on CAR T-cell treatment and led us to studies to understand what’s changing in the microenvironment,” Brown stated.

Using congenic mouse strains CD45.1 and CD45.2 to differentiate adoptively transferred T cells and endogenous T cells, respectively, Alizadeh and the other investigators looked at the changes in the T cell compartment after CAR T-cell therapy. When the CAR T cells were adoptively transferred, they became activated and proliferated, which was shown by the Ki67, CD69, and GZMB-positive T cell counts, which Brown said was to be expected. Mice who were given CAR T cells also had stimulated endogenous T cell activation in the tumor microenvironment after treatment.

The resident myeloid activation in glioblastoma was induced with CAR T-cell therapy in major histocompatibility complex class I and II. There was greater activation with CAR T in these myeloid populations, shown by CD86-positive myeloid cells and IFNγ-positive myeloid cells.

Single-cell RNA sequencing showed that myeloid populations upregulated the expression of genes associated with antigen presentation, Brown said. There was also an increase in the expression of IFNγ stimulation.

Because of these findings, the investigators looked at the role of IFNγ in these responses. They analyzed IFNγ receptor knockout host mice using wild-type CAR T cells and wild-type tumor cells and models that did not respond to IFNγ in the tumor microenvironment. They observed that the host immune cells lacked the ability to respond to IFNγ; those mice had a worse response to CAR T cells, according to Brown.

“Productive CAR T-cell therapy required that the immune landscape or the immune cells within the tumor responded to IFNγ,” Brown said. “When they didn’t, we saw decreased activation of myeloid cells within the tumor and decreased activation of host T cell populations.”

Through induction of endogenous antitumor immunity, investigators hypothesize that challenges with CAR T-cell therapy for solid tumor can be overcome.

“What we’ve shown is that in productive CAR T-cell therapy in solid tumors, not only is antigen-dependent killing important, but we believe the indirect effects, mediated through the production of IFNγ, the stimulation of resident macrophages, and induction of endogenous T cells is also very critical in this response,” Brown concluded.

Brown CE, Alizadeh D, Jonsson V, et al. CAR T cell therapy reshapes the tumor microenvironment to promote host antitumor immune responses in glioblastoma. Poster presented at: American Association of Cancer Research (AACR) Annual Meeting 2021; April 9-14, 2021; virtual. https://bit.ly/3v79JaX. Accessed April 15, 2021.

Chimeric antigen receptor T-cell therapy mediates antigen-dependent and
 -independent antitumor effects, and CAR T-cell activation of host antitumor immunity is critical for productive solid tumor CAR T immunotherapy.

Dylann Cohn-Emery | Authors

Articles

Pembrolizumab Achieves Prespecified Event-Free Survival in High-Risk TNBC

Prior Comorbidities Predict Risk of Treatment-Emergent Atrial Fibrillation in CLL

Response to Targeted Therapy Increased From 2006 to 2020 in Patients With Cancer

Immune System Plays Important Role in CAR T Cell Responses in Glioblastoma Models