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In July 2021, the FDA granted full regulatory approval to enfortumab vedotin-ejfv (Padcev) for the treatment of patients with relapsed or refractory advanced/metastatic urothelial carcinoma.

 Previously awarded accelerated approval for this indication in 2019,

 enfortumab vedotin is the first drug to target the nectin-4 protein, a key regulator of cell adhesion.

An antibody-drug conjugate (ADC), enfortumab vedotin exploits the high levels of nectin-4 expression in urothelial carcinoma to enable targeted deployment of a cytotoxic warhead in tumor cells.

 Specifically, enfortumab vedotin is approved for patients with locally advanced/metastatic urothelial carcinoma who have been previously treated with a PD-1/PD-L1 immune checkpoint inhibitor (ICI) and platinum-containing chemotherapy or are ineligible for cisplatin-containing chemotherapy after receiving 1 or more prior lines of therapy.

Beyond enfortumab vedotin, the devel-opment of nectin-4–targeted drugs is in its infancy; other agents are in the preclinical or very early clinical stages of development. However, burgeoning interest in this target reflects the potential oncogenic role of nectin-4 across a broad range of malignancies.

Furthermore, there is growing appreciation of the role of nectins in the antitumor immune response through their interaction with immune checkpoint receptors, including TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains).

Most ongoing clinical trials exploring nectin-4 as a target involve studies of enfortumab vedotin and its potential synergy with ICIs in bladder cancer, while several other early-phase studies are testing novel agents in solid tumors (

). Meanwhile, agonistic nectin-4–specific monoclonal antibodies could have ICI functionality in their own right.

The nectin family of proteins, whose name derives from the Latin necto, meaning “to connect,” are cell adhesion molecules that are essential to forming physical connections between neighboring cells to enable intercellular communication, migration, and other vital cellular processes.

Among the 4 human nectin proteins, nectin-4 is unique in that its expression is largely restricted to placental and embryonic tissues. Importantly, however, in contrast to healthy adult tissue, many types of cancer have high nectin-4 expression.

In urothelial carcinoma, moderate to high levels of nectin-4 were observed in 60% of bladder cancer samples in 1 study

 and in 34% of upper tract urothelial carcinoma samples in another.

 In upper tract urothelial carcinoma, high levels of nectin-4 were associated with a significantly higher risk of progression (

 = .04) and were an independent predictor of disease progression in high-risk disease (HR, 3.32; 95% CI, 1.20-7.98; 

Other cancer types in which nectin-4 overexpression has been found in a significant portion of samples include breast, ovarian, cervical, colorectal, esophageal, gastric, lung, liver, and thyroid cancer. Studies have suggested that nectin-4 expression may predict poor prognosis in several types of cancer; however, its analytical and clinical validity have not been fully established and its clinical utility as a prognostic marker remains to be confirmed.

High nectin-4 expression is associated with increased tumor size, grade, and invasiveness, as well as reduced patient survival, in some cancer types. In addition, nectin-4 overexpression may be linked to chemotherapy resistance.

 A recent study also demonstrated that nectin-4 expression was upregulated in BRAF inhibitor–resistant melanoma cells.

As a result of its cancer-specific expression, nectin-4 has emerged as a highly promising therapeutic target. The main focus of drug development has been in advanced/metastatic urothelial carcinoma, in which 5-year survival rates are abysmally low despite the availability of novel immunotherapeutic options.

The standard of care for patients with advanced/metastatic urothelial carcinoma is platinum-based chemotherapy; however, a substantial number of patients are ineligible for chemotherapy. Patients with recurrent disease or whose tumors express PD-L1 may be treated with ICIs, but only a minority of patients experience durable responses; response rates are particularly low among patients with visceral metastases.

Enfortumab vedotin, formerly ASG-22CE, is an ADC composed of a nectin-4–targeted monoclonal antibody conjugated via a cleavable linker to a microtubule-disrupting cytotoxic drug, monomethyl auristatin E (MMAE). It exploits nectin-4 expression in urothelial carcinoma to target the delivery of MMAE to tumor cells (

). Once the nectin-4 antibody component of the drug binds to nectin-4 on the membrane, the ADC is taken up into the cell, and the linker is cleaved within the lysosome, releasing MMAE, which binds to tubulin, disrupting microtubule assembly and driving cell cycle arrest and apoptosis.

Accelerated approval of enfortumab vedotin for the treatment of locally advanced/ metastatic urothelial carcinoma in 20192 was based largely on the results of 2 clinical trials, EV-101 and EV-201.

 EV-101 (NCT02091999) was a phase 1 dose-escalation and dose-expansion study of enfortumab vedotin in patients with previously treated advanced/metastatic solid tumors.

Initially, trial eligibility requirements included positive tumor nectin-4 expression per immunohistochemistry (IHC) analysis; however, the protocol was amended to remove this criterion after nectin-4 expression was identified in almost all samples (median IHC H-score, 290; range, 0-300). In cohort A, patients were treated with enfortumab vedotin monotherapy at escalating doses up to 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles. In cohort B, dose expansion was performed in 3 patient populations: those with urothelial carcinoma, non–small cell lung cancer, or ovarian cancer. Cohort C involved dose expansion in patients with metastatic urothelial carcinoma that had progressed following ICI therapy.

Among the 112 patients with metastatic urothelial carcinoma who were treated with enfortumab vedotin at 1.25 mg/kg, the overall response rate (ORR) was 43% (95% CI, 33.6%-52.6%), with a median duration of response (DOR) of 7.4 months (95% CI, 5.6-9.6) and median overall survival (OS) of 12.3 months (95% CI, 9.3-15.3). Similar response rates were observed across all patient subgroups, including patients aged 75 years or older, those with liver metastases, and those with upper tract disease. The most common treatment-related adverse events (TRAEs) were rash, peripheral neuropathy, fatigue, alopecia, and nausea, predominantly grade 1 or 2 in severity.

EV-201 (NCT03219333) was a phase 2 single-arm trial in which enfortumab vedotin was tested in patients with metastatic urothelial carcinoma who had been previously treated with both platinum-based chemotherapy and ICIs (cohort 1) or with an ICI only (cohort 2). Patients were treated with a dose of 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles. Although nectin-4 positivity was not a requirement for enrollment, nectin-4 expression (median IHC H score, 290; range, 14-300) was identified in 100% of the 120 patient samples that were collected.

In cohort 1 (n = 125), the ORR was 44% (95% CI, 35.1%-53.2%), including complete responses (CRs) in 12% of patients, with a median DOR of 7.6 months (95% CI, 4.93-7.46). Similar ORRs were observed across prespecified patient subgroups, including patients with liver metastases. The most common TRAEs were fatigue, alopecia, decreased appetite, dysgeusia, and peripheral neuropathy.

 Results from cohort 2 (n = 89) were also recently published; at a median follow-up of 13.4 months, the ORR was 52% (95% CI, 41%-62%), with CRs in 20% of patients.

Continued approval of enfortumab vedotin was premised on the demonstration of confirmed efficacy in randomized phase 3 trials. In the phase 3 EV-301 trial (NCT03474107), enfortumab vedotin was compared with standard chemotherapy in patients (n = 608) with locally advanced or metastatic urothelial carcinoma previously treated with platinum-based chemotherapy and an ICI. Patients were randomized 1:1 to enfortumab vedotin at a dose of 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles or investigator’s choice of chemotherapy (docetaxel; n = 117, paclitaxel; n = 112, or vinflunine [where approved for use]; n = 78) administered on day 1 of 21-day cycles.

At a median follow-up of 11.1 months, enfortumab vedotin was found to significantly improve OS and progression-free survival (PFS) compared with chemotherapy in this patient population, reducing the risk of death by 30% and the risk of progression or death by 38%. Median OS was 12.88 months (95% CI, 10.58-15.21) in the enfortumab vedotin arm compared with 8.97 months (95% CI, 8.05-10.74) in the chemotherapy arm (HR, 0.70; 95% CI, 0.56-0.89; 

 = .001), and median PFS was 5.55 months (95% CI, 5.32-5.82) vs 3.71 months (95% CI, 3.52-3.94), which translated into an HR of 0.62 (95% CI, 0.51-0.75; 

 < .001). Patients treated with enfortumab vedotin also had a significantly higher ORR (40.6% vs 17.9%; 

 < .001) and a numerically higher CR rate (4.9% vs 2.7%).

The incidence of TRAEs of any grade (93.9% vs 91.8%) or of grade 3 and higher (51.4% vs 49.8%), as well as the rates of dose reduction, interruption, and discontinuation resulting from TRAEs, were similar in the 2 study arms. The most common grade 3 and higher TRAEs experienced by patients treated with enfortumab vedotin were maculopapular rash, fatigue, decreased neutrophil count, and neutropenia.

In an update presented at the European Society for Medical Oncology Congress 2021, findings showed that the survival benefit associated with enfortumab vedotin treatment was maintained across hard-to-treat patient subgroups, including patients aged 65 years and older and those with liver metastases, upper tract disease, and lack of response to prior ICI therapy.

In numerous ongoing clinical trials, investigators are evaluating the potential of enfortumab vedotin in the frontline setting for patients with advanced/metastatic urothelial carcinoma (EV-302; NCT04223856), as well as earlier in the course of disease in the perioperative setting (VOLGA; NCT04960709 and EV-304; NCT04700124).

Results from a cohort of patients enrolled in the ongoing EV-103 trial (NCT03288545) were recently published. EV-103 is a phase 1/2 trial evaluating enfortumab vedotin as monotherapy or in combination with other cancer drugs as first- and second-line treatment for patients with advanced/metastatic disease. After more than 2 years of follow-up, 45 cisplatin-ineligible patients who were treated with the combination of enfortumab vedotin and the PD-1 ICI pembrolizumab (Keytruda), in the frontline setting had an ORR of 73.3% (95% CI, 58.1%85.4%), including CRs in 17.8% of patients, with a median DOR of 25.6 months (95% CI, 8.3-not reached) and median PFS of 12.3 months (95% CI, 8.0-not reached). Among patients with liver metastases, the ORR was 57.1%. The most common TRAEs were peripheral neuropathy, fatigue, and alopecia.

On the basis of these results, this combination was granted a breakthrough therapy designation by the FDA for the frontline treatment of patients with cisplatin-ineligible metastatic urothelial carcinoma.

An increasingly recognized aspect of nectin family members is their role in immune modulation. Several nectins and nectin-like (Necl) molecules act as ligands for costimulatory and coinhibitory immune checkpoint receptors, and in recent years, the nectin family banner has been widened to encompass these receptors, most notably TIGIT.

TIGIT, a coinhibitory immune checkpoint receptor expressed on the surface of multiple immune cell types, exerts an immunosuppressive function. Alongside the costimulatory receptor CD226, TIGIT forms an immune checkpoint pathway that is analogous to the prototypical CD28/CTLA-4 checkpoint pathway. The ligands for TIGIT include CD112 (also known as nectin-2) and CD155 (Necl-5).

TIGIT has emerged as a promising target for the next generation of ICIs. Several TIGIT-targeted drugs are in clinical development, including Roche’s tiragolumab (MTIG719A) and Merck’s vibostolimab (MK-7684).

 A recent study identif ied nectin-4 as a novel ligand for TIGIT. Unlike other TIGIT ligands, which bind to additional receptors, nectin-4 appears to exclusively bind to TIGIT; this interaction was shown to inhibit the activity of natural killer cells.

Thus, in addition to providing specificity in tumor targeting, nectin-4–targeted therapies could also prove to have immunotherapeutic properties. The vast majority of ongoing clinical trials of enfortumab vedotin and development of novel nectin-4–targeted therapies are focusing on combining these drugs with ICIs in the hopes of eliciting synergistic activity.

Agents in development include Bicycle Therapeutics’ BT8009, whose design is similar to an ADC. The agent is conjugated to an MMAE but uses the company’s proprietary bicyclic peptides instead of an antibody to target nectin-4. Investigators hypothesize that the more rapid plasma clearance achieved by the small bicyclic peptide will reduce BT8009’s systemic toxicity compared with bulkier antibody-based agents.

Jane de Lartigue, PhD, is a freelance medical writer based in Gainesville, Florida.

FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. Updated July 9, 2021. Accessed October 8, 2021. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-enfortumab-vedotin-ejfv-locally-advanced-or-metastatic-urothelial-cancer

FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. FDA. Updated December 19, 2019. Accessed October 13, 2021. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-metastatic-urothelial-cancer

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Articles

Most ongoing clinical trials exploring nectin-4 as a target involve studies of enfortumab vedotin and its potential synergy with immune checkpoint inhibitors in bladder cancer, while several other early-phase studies are testing novel agents in solid tumors.

Nectin-4 Emerges as a Therapeutic Target in Urothelial Carcinoma and Beyond

Data quality is essential to improving the United States health care system. But what is data quality? Basically, it is about extracting value for patients, clinicians, and payers. High-quality data are both usable and actionable, whereas low-quality data, such as duplicate records, missing patient names, or obsolete information, create barriers to care delivery and billing/payment issues. These inefficiencies result in monetary losses across the health care system.

Unfortunately, health care has lagged virtually every other industry in leveraging data for strategic and operational advantage. This is not for lack of data—more patient health data are being captured today by medical equipment, digital devices, and apps than ever before. If data are gold, the health care industry is sitting on top of a gold mine.

In general, the industry has done a poor job of mining and refining this gold ore of data to the point of being useful. This is a wasted opportunity because quality data would provide value to all health care stakeholders, including hospitals, payers, health information exchanges, laboratories, and patients.

Poor data quality have negative ramifications throughout health care. The way we bring new medications to market is a great case in point. The first phase is identifying and developing the medication, a process that comprises less than 20% of the cost of drug development. Next comes clinical trials, which account for most drug development costs.

Clinical trials are long and arduous. Worse, from a data quality standpoint, data still are collected on paper, transferred to computer, and typically not associated with other data sets for similar types of patients or even other patients in that clinical trial. If all this information was easily available and automated, clinical trials would cost less than 10% of what they do now.

In clinical practice, there is a significant lack of aggregated data for patients, leaving clinicians knowing only part of a patient’s story. Further, when a physician sees a patient at the hospital, they need the patient’s ambulatory outpatient records to make sound, evidence-based decisions about appropriate treatment. In far too many cases, however, the data that would inform clinicians at the point of care are trapped in siloes scattered across the health care landscape.

Health care has not availed itself of advanced digital technologies such as artificial intelligence (AI) and machine learning, which are being used to transform many other industries. This is in large part because these tools are either not accessible or the quality of health data is so poor that intelligent machines would struggle to process and analyze it for actionable insights into patient care.

In contrast, access to quality health care data would create scenarios in which AI and machine learning can quickly provide clinicians with information at the point of care that enables them to educate patients about their specific condition, offer referrals to appropriate specialists, suggest new medications, and improve outcomes. With the right data and insights, clinicians may be able to match the patient with a clinical trial that could save the patient’s life.

Low-quality data are also a problem for payers because they need data to make decisions, regardless of the condition. Data collection starts when a patient receives a diagnosis, yet the payer may not be aware of it for weeks. So, for example, a patient who receives a diagnosis of cancer may suddenly have to find a specialist and determine whether the practice takes their insurance.

However, if a payer finds out right away that this patient has cancer, the payer can help guide the patient to the right provider, alleviating some of the burden of financial concerns related to medical treatment.

There are 3 main steps to achieving high-quality data. The first is ensuring access to the data the clinician needs. There are still many legacy systems in health care, which house most medical records on an organization’s servers and not on a cloud platform, where they could be more easily accessed and aggregated by authorized users. Although interoperability and data sharing have improved in the health care setting in recent years, integrations are being built one at a time. Bringing data into a central database—where that information can be turned into gold—remains a challenge.

The next step involves identity management. Much of the value in health data comes from the ability to document longitudinal change in individual patients. Clinicians may, for example, want to see how medications affect lab results for a particular patient. Even if they could connect disparate data sources and have the data funnel into a single database, they cannot associate the data with a specific patient. With effective identity management, it is possible to create a longitudinal patient record that can bring huge clinical and efficiency benefits.

The third phase of improving data quality is to make the data usable or actionable. Once the longitudinal record of accurate patient data is created, it must be organized and easy for clinicians to locate and read. This requires a process called data normalization. Health data can come from multiple sources (ie, electronic health records, laboratories, pharmacy systems, etc), all of which may use different coding for a medical procedure, different terms for a certain test, or even different language to categorize genders. Data normalization creates a common terminology that enables the semantic interoperability necessary to make data actionable.

There’s no magic bullet for improving health care data quality. It will require a joint effort and the innovation inherent in the free market. There will be companies that help us collect and connect to data, and there will be companies and entities that help us connect to data. There will be technologies that identify the data and others that will normalize the data, and there will be companies that provide quality databases that health care stakeholders can use to perform advanced analytics. The end result will be a health care system that provides better care at a lower cost.

Oleg Bess, MD, is CEO and cofounder of 4medica, which provides clinical data management and health care interoperability software and services.

Oleg Bess, MD, explains why data quality is essential to improving the United States health care system.

Data Quality Issues Plague the US Health Care System

Expression of B7-H3, a novel molecule of the B7 family, has been associated with undesirable treatment outcomes and has a potential role in the activation and inhibition of immune cell response.

The investigational monoclonal antibody enoblituzumab has demonstrated activity in preclinical studies and in combination with pembrolizumab (Keytruda) in phase 1/2 studies in patients with checkpoint inhibitor–naïve head and neck squamous cell carcinoma (HNSCC) and non–small cell lung cancer (NSCLC).

Investigators have demonstrated that more than 50% of patients across tumor types were positive for B7-H3 expression via immunohistochemistry. Specifically, for those with NSCLC (74% positive expression), B7-H3 correlated with ineffective anti–PD-1 therapy, and for those with cutaneous squamous cell carcinoma (85% positive expression), B7-H3 expression was higher in those who were immunocompetent.

Patients with HNSCC who have relapsed or have metastatic disease have survival outcomes of approximately less than 1 year with the best available therapies.

 Activity has been observed with PD-1 inhibitors; however, investigators are pursuing synergistic pathways which may lead to improved outcomes with combination regimens.

B7-H3, also known as CD276, has limited expression in normal tissue, making it an attractive target for therapeutic development. Enoblituzumab is a fragment crystallizable (Fc) optimized humanized IgG1 monoclonal antibody with an antigen-binding fragment with a high affinity for B7-H3. Further, the Fc structure has a high affinity for activating CD16A and a low affinity for inhibiting CD32B, with the potential enhancement of adaptive immune responses.

In a phase 1 study (NCT01391143) enoblituzumab had a tolerable safety profile with no drug-related adverse effects (AEs) that led to study discontinuation and no maximum tolerated dose was defined up to 15 mg/kg among patients with B7-H3 expressing cancers. Patients were heavily pretreated with a median of 3 prior lines of therapy (range, 0-7) and experienced disease stabilization over more than 12 weeks; tumor shrinkage ranged from 2% to 69% across tumor types.

Efficacy data from the phase 1/2 CP-MGA271-03 study (NCT02475213) demonstrated that anti–B7-H3 and anti–PD-1 blockade with enoblituzumab and pembrolizumab nearly doubled overall response rates compared with anti–PD-1 blockade alone in comparator studies. Investigators enrolled patients with HNSCC, NSCLC, melanoma, and urothelial cancer to the study. In terms of safety, 27.1% of patients (N = 133) experienced grade 3 or higher AEs, the most common of which were infusion-related reactions (6.8%). An AE of special interest was pneumonitis, which was reported in 3.8% of patients with 2 patients having a grade 3 or higher event; pneumonitis led to death in 1 patient.

 Investigators noted that the AEs were consistent with previously reported data for the single agents.

Patients with HNSCC and NSCLC were stratified by those who received prior anti–PD-1/PD-L1 therapy and those who were treatment naïve. Among 18 treatment-naïve patients with HNSCC and were evaluable for response, 33.3% had a partial response or complete response vs no responses reported for the 19 patients who received prior anti–PD-1/PD-L1 therapy. Stable disease was reported in 27.8% and 47.9% of patients, respectively.

Among responders, 15 had B7-H3 expression of 10% or higher on tumor cells per immunohistochemistry. Among these individuals, 40.0% had a complete or partial response and 73.3% had a complete response, partial response, or stable disease at data cutoff.

Investigators compared the response rate elicited with the combination in the treatment-naïve cohort with comparator studies and demonstrated that it was nearly double of that in those who received single-agent anti–PD-1 blockage alone (

 Although the populations in the combination study were smaller, the efficacy data warrant further investigative efforts as a potential strategy to improve tumor responses.

Combinations With Enoblituzumab Move Ahead 

Investigators hypothesize that the simultaneous targeting of B7-H3 and PD-1 or B7-H3 and PD-1 and LAG3 may have the potential to sustain the immune activation and antitumor activity that is mediated by enoblituzumab based on in vitro data.

Therefore, the proof-of-concept phase 2 CP-MGA271-06 study (NCT04634825) was initiated to evaluate enoblituzumab in combination with retifanlimab or tebotelimab for the treatment of patients with recurrent or metastatic HNSCC not curable by local therapy with no prior systemic therapy for HNSCC in the recurrent or metastatic setting (

Retifanlimab is an investigational, humanized, anti–PD-1 monoclonal antibody that binds to PD-1 with affinity 4 times greater than nivolumab (Opdivo) and 6 times greater than pembrolizumab.

 Tebotelimab is a bispecific DART molecule engineered against PD-1 and LAG3, disrupting the pathways that so that T-cell function may be restored. The agent blocks binding of PD-1 or PD-L1 to PD-1 as well as major histocompatibility complex class II to LAG3.

Patients will be assessed for PD-L1 expression and stratified into cohorts based on combined positive score (CPS). Investigators plan to enroll approximately 50 patients with a CPS of 1 or higher to receive enoblituzumab at 15 mg/kg plus retifanlimab at 375 mg every 3 weeks for up to 35 cycles. Approximately 30 patients with a CPS of less than 1 will receive enoblituzumab at 15 mg/kg plus tebotelimab at 600 mg every 3 weeks for up to 35 cycles. Safety evaluations for dose-limiting toxicities will be conducted through day 7 of cycle 2 for the first 12 patients.

The primary end point is objective response rate, with secondary end points of progression-free survival, disease control rate, duration of response, and overall survival. Exploratory objectives of the trial include relationships between pharmacokinetics, pharmacodynamics, safety, and antitumor activity; relationships between PD-1, PD-L1, B7-H3, and LAG3 expression on tumor cells and response; and peripheral biomarkers and correlation with potential clinical response.

Patients whose primary tumor site is the upper esophagus, salivary gland, or nasopharynx of any histology or those with disease suitable for local therapy with curative intent are excluded from enrollment. Further, patients who have received prior therapy with an anti–B7-H3, anti–PD-1, anti-PD-L1, anti–PD-L2, or anti-LAG3 agent are not eligible.

Yang S, Wei W, Zhao Q. B7-H3, a checkpoint molecule, as a tar-get for cancer immunotherapy. 

. 2020;16(11):1767-1773. doi:10.7150/ijbs.41105

Obara G, Sun J, Loo D, Bohac C. Phase II trial of enoblituzum-ab plus retifanlimab or tebotelimab in first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M SCCHN). 

. 2021;32(suppl 5):S814. doi:10.1016/j.annonc.2021.08.1336

Powderly J, Cote G, Flaherty K, et al. Interim results of an on-going phase I, dose escalation study of MGA271 (Fc-optimized humanized anti-B7-H3 monoclonal antibody) in patients with refractory B7-H3-expressing neoplasms or neoplasms whose vasculature expresses B7-H3. 

. 2015;3(sup-pl 2):O8. doi:10.1186/2051-1426-3-S2-O8

Aggarwal C, Joshua A, Ferris RL, et al. A phase 1, open-label, dose-escalation study of enoblituzumab in combination with pembrolizumab in patients with select solid tumors. Presented at: Society for Immunotherapy of Cancer Meeting 2018; November 7-11, 2018; Washington DC. Abstract O24. 

Enoblituzumab plus retifanlimab or tebotelimab in head and neck cancer. ClinicalTrials.gov. Updated October 12, 2021. Accessed November 11, 2021. https://clinicaltrials.gov/ct2/show/NCT04634825 

Retifanlimab (PD-1). MacroGenics. Accessed November 11, 2021. https://macrogenics.com/mga012-pd-1/7. Tebotelimab (PD-1 × LAG-3). MacroGenics. Accessed November 11, 2021. https://macrogenics.com/mgd013-pd-1-x-lag-3/

The investigational monoclonal antibody enoblituzumab has demonstrated activity in preclinical studies and in combination with pembrolizumab in phase 1/2 studies in patients with checkpoint inhibitor–naïve head and neck squamous cell carcinoma and non–small cell lung cancer.

Novel Combination Looks to Capitalize on Synergy of B7-H3/PD-1 Blockade

Abemaciclib, a CDK4/6 inhibitor, has been approved in combination with tamoxifen or an aromatase inhibitor for the adjuvant treatment of adult patients with hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence and a Ki-67 score of at least 20%, as determined by an FDA-approved test, based on data from the phase 3 MonarchE trial (NCT03155997). 

The 36-month invasive disease-free survival rate among patients treated with abemaciclib plus tamoxifen or an aromatase inhibitor (n = 1017) was 86.1% (95% CI, 82.8%-88.8%) compared with 79% (95% CI, 75.3%-82.3%) in patients treated with tamoxifen or an aromatase inhibitor alone (n = 986). Approximately 16% of patients in the control group experienced an event vs 10.2% in the experimental arm (HR 0.0626; 95% CI, 0.488-0.803; P = .0042). 

, Stephen Johnston, MD, PhD, head of Medical Oncology and head of the Breast Unit at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research in London, England, provided insight on the effect the approval of the CDK4/6 inhibitor has for patients with early breast cancer and how it will advance investigative efforts in this space.

What was the clinical rationale for studying this combination in this patient population?

In the MonarchE trial, we looked at patients who were deemed to be at high risk of recurrence following a diagnosis of [hormone receptor–] positive, HER2-negative early breast cancer. We were specifically selecting those who had lymph node–positive disease. We know they’re at higher risk. The layers of risk on top of that [baseline] were addressed as [either] 4 or more [positive] nodes, or if they had 1 to 3 [positive] lymph nodes. [Also,] patients had additional risks, such as a large tumor, high grade, or high proliferation. Despite the best standard of care, we estimated this population would, on average, [experience] relapse at a rate from 20% to 30% in the first 3 to 5 years, so there was room for improvement.

CDK inhibitors have already been shown to add [benefit] to endocrine therapy in advanced disease, as they overcome endocrine resistance and they control the cancer for longer. The question was: In early breast cancer, could we select an at-risk population and show that adding [a CDK inhibitor] for 2 years in addition to their endocrine therapy would [reduce the rate of] early recurrences in the f irst 2 to 3 years?

Please speak on how this approval will affect the treatment landscape for early breast cancer. 

This is the first CDK4/6 inhibitor [approved] in early breast cancer, and that’s based on the level of efficacy seen in the MonarchE trial. The FDA label has specifically added the high–Ki-67 group, which was approximately 2500 patients in the trial, because they had an even greater risk of recurrence if they had an increased [number of positive] lymph nodes and other risk factors. That’s a group that derived a very significant gain in recurrent-free survival at the 3-year point.

This is a particularly high-risk group, where [the FDA] feels that the early recurrences in the first few years potentially could be prevented by the addition of the CDK inhibitor. [The approval] represents a very significant milestone in hormone positive–early breast cancer. 

[With the approval,] we now have a new endocrine-based treatment, which we have not [seen an] approval for in nearly 20 years. It’s a paradigm shift because the last new treatment were the aromatase inhibitors in 2002. This represents our progress in understanding primary endocrine resistance, [identifying] patients who are destined to relapse despite the best therapies and developing interventions to stop those early recurrences. 

This is a highly significant milestone for the small group of patients with highrisk disease, for whom endocrine therapy [alone] isn’t going to be the solution. We can make a significant difference for them. For many patients, endocrine therapy alone plus their current treatments can cure them. But, for around 15% of all patients with [hormone receptor–]positive breast cancer, they are destined to relapse relatively early despite endocrine treatment. For that group of patients, which we believe we can now identify, this makes for a big improvement in their outcome.

What does the future hold for abemaciclib in combination with endocrine therapy? 

There are approximately 6 or 7 ongoing studies with CDK inhibitors in the early breast cancer setting, looking to see if we can further refine the group of patients who benefit. Trials in both a neoadjuvant and adjuvant setting are [evaluating CDK inhibitors] head-to-head against chemotherapy because chemotherapy is not always the answer for luminal hormone positivebreast cancer. That will be important because you could spare the toxicity of chemotherapy with this effective combination if it can be proven to be as effective or better. 

Other studies are to refine the selection of endocrine-resistant disease. [Investigators are using a] technique of very short-term exposure to a hormone treatment in the 2 or 3 weeks before surgery and measuring Ki-67 [expression] to see whether hormone treatment switches that off. If it does, hormone treatment alone can be very good. However, hormone treatment will not switch off cell proliferation in approximately 20% of patients. [To overcome this,] investigators of the POETIC-A study [NCT04584853] will identify those where the proliferation is not being switched off and randomize them to abemaciclib [or endocrine therapy] after [surgery]. 

The label [indicates abemaciclib] for large, node-positive tumors. The [patients in POETIC-A] may have smaller tumors or node-negative disease, [representative of] a group of patients with biologically resistant tumors to endocrine therapy, who may not have high clinical pathological risk factors. That may be the next setting where this drug could be refined to have a niche role.

Verzenio. Prescribing information. Eli Lilly and Company; 2021. Accessed November 5, 2021. bit.ly/3BUraOU

Stephen Johnston, MD, PhD, provides insight on the effect the approval of the CDK4/6 inhibitor abemaciclib has for patients with early breast cancer and how it will advance investigative efforts in this space.

Abemaciclib Becomes First Agent of its Kind Approved for Adjuvant Treatment of Early Breast Cancer

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal disorders of hematopoietic stem cells that lead to dysplasia and ineffective hematopoiesis in the bone marrow, with older patients (> 65 years) most frequently affected.

 The disease course is variable and not all patients may require treatment initially, particularly if they are asymptomatic. In 2017, the World Health Organization published a revised classification of myeloid neoplasms to incorporate genetic information, which resulted in broadening the subset of cases classified as MDS with ring sideroblasts, and to improve patient risk stratification to enable better overall treatment.

 More recently, several agents for specific patient subgroups have been approved by the FDA, including for patients with very low-risk to high-risk MDS, and many other novel agents with unique mechanisms of action are on the horizon.

, a panel of hematologic cancer experts shared their insights on the most recent FDA-approved agents for MDS, including luspatercept (Reblozyl) and decitabine/cedazuridine (Inqovi), both of which were approved in 2020.

 They also examined some novel emerging treatments, including pevonedistat, magrolimab, and venetoclax (Venclexta), all 3 of which have been granted FDA breakthrough therapy designation as MDS treatments for patients with higher-risk disease,

 although pevonedistat’s future in MDS has become uncertain because it recently missed achieving its primary end point of event-free survival (EFS) in the phase 3 PANTHER trial (NCT03268954).

Luspatercept is a first-in-class erythroid maturation agent.9 Impaired erythroid maturation contrib-utes to ineffective erythropoiesis, resulting in low production of red blood cells (RBCs) and anemia. Luspatercept enhances late-stage erythropoiesis by binding several endogenous transforming growth factor-β superfamily ligands, thereby diminishing SMAD2/3 signaling.

 SMAD2/3 proteins have been found to be constitutively acti-vated and overexpressed in MDS bone marrow precursors.

“The exciting thing about luspatercept is that it was the first drug we got approved for MDS [in over a decade], so that by itself is a milestone for all the people who have worked on this,” Rami Komrokji, MD, said. Luspatercept is approved for the treatment of anemia failing an erythropoiesis-stimulating agent and requiring at least 2 RBC units over 8 weeks in adult patients with very low–risk to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis.

The FDA approval of luspatercept was based on data from the double-blind phase 3 MEDALIST trial (NCT02631070), which randomly assigned 229 patients with very low–risk, low-risk, or intermediate-risk MDS with ring sideroblasts requiring regular RBC transfusions to receive either luspatercept at a dosage of 1.0 mg/kg to 1.75 mg/kg (n = 153) or placebo (n = 76), administered subcutaneously every 3 weeks.

 Transfusion independence for at least 8 weeks was achieved in 38% of the patients in the luspatercept arm vs 13% of those in the placebo arm (P < .001). A significantly higher percentage of patients in the luspatercept arm than in the placebo arm met the secondary end point of transfusion independence for at least 12 weeks (28% vs 8%, respectively, for weeks 1 through 24; 33% vs 12%, respectively, for weeks 1 through 48; P < .001 for both comparisons).

“The real benefit of transfusion independency was in patients who were not heavily transfusion dependent,” Komrokji said. “Once patients get into the 6 to 8 units every other month, those patients may benefit a little bit in transfusion reduction, but not really transfusion independency. So, in my algorithm now, if patients have had an adequate trial of ESA [erythropoietin-stimulating agents] and we are now moving to the next step, I ask whether they have ring sideroblasts. If they do, I try to introduce [luspatercept] a little bit earlier, before the patients are heavily transfusion dependent.”

In the MEDALIST trial, the most common luspatercept-associated adverse events (AEs) of any grade included fatigue, diarrhea, asthenia, nausea, and dizziness, with the incidence of AEs decreasing over time. “We have had a couple of patients who had to come off [treatment], but in general it was very well tolerated,” Komrokji said. He emphasized the importance of following the escalated dosing outlined in the package insert for patients who are not RBC transfusion free after 2 consecutive doses (6 weeks) at the recommended 1-mg/kg starting dose.

Decitabine/cedazuridine is a fixed-dose oral combination therapy that pairs a nucleoside metabolic inhibitor (ie, decitabine) with a novel cytidine deaminase inhibitor (ie, cedazuridine).

 It is indicated for adult patients with previously treated or untreated, de novo and secondary MDS with the following French-American-British subtypes: refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia (CMML).

 It is also indicated for patients with MDS who fall into intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

FDA approval of decitabine/cedazuridine was based on data from 2 open-label, randomized, crossover trials: the phase 1/2 ASTX727-01-B trial (NCT02103478), which included 80 adult patients with MDS or CMML, and the phase 3 ASTX727-02 trial (NCT03306264), which included 133 adult patients with MDS or CMML.

 “Pharmacokinetically and from a response perspective, it looks like [decitabine/cedazuridine is] the same as decitabine,” Gail J. Roboz, MD, said. She explained that the addition of cedazuridine allows oral dosing by preventing the decitabine from being completely broken down by the gastrointestinal tract and liver, which would limit decitabine’s oral bioavailability.

In the clinical trials, oral decitabine/ cedazuridine administered as a 100/35-mg fixed-dose tablet was found to provide equivalent decitabine exposure to intravenous (IV) decitabine 20 mg/m2 when both were administered over 5 days.

 The decitabine area under the curve (AUC) 5-day geometric mean estimate was 856 from the oral combination and 865 from IV decitabine, resulting in an oral/IV AUC ratio of 98.9%.

 Additionally, clinical responses were consistent with those seen in patients receiving IV decitabine. The complete response (CR) rate for the oral combination was 18% in the 01-B trial and 21% in the 02 trial, with median durations of response of 8.7 months and 7.5 months, respectively.

 Among the patients who were dependent on RBC and/or platelet transfusions at baseline, approximately 50% in both trials became independent of RBC and platelet transfusions during any 56-day postbaseline period, with greater than 60% remaining transfusion independent during any 56-day postbaseline period.

The tolerability of oral decitabine/cedazuridine was consistent with that of IV decitabine.4 The most common AEs and laboratory abnormalities with the oral combination are summarized in the TABLE.

“Oral decitabine is really a major improvement in delivery and I’m prescribing it to my patients, but the message for the community is: You still need to bring those patients in every week and check your counts,” Komrokji said. “The fact that it’s a pill doesn’t mean you see them next month. Bring them back every week as if you are doing IV or subcutaneous hypomethylating agents.”

During a recent OncLive Peer Exchange®, a panel of hematologic cancer experts shared their insights on the most recent FDA-approved agents for MDS, including luspatercept and decitabine/cedazuridine (Inqovi), both of which were approved in 2020.

Vol. 22/No. 23 | Oncology Live®

Nectin-4 Emerges as a Therapeutic Target in Urothelial Carcinoma and Beyond

Data Quality Issues Plague the US Health Care System

Novel Combination Looks to Capitalize on Synergy of B7-H3/PD-1 Blockade

Abemaciclib Becomes First Agent of its Kind Approved for Adjuvant Treatment of Early Breast Cancer

Novel Agents Shake Up Myelodysplastic Syndrome Treatment Landscape

Pembrolizumab Combination Advances Standard of Care in TNBC

It Is Time to Reexamine Control Arms in Phase 3 Trials