Evidence-Based Oncology
June 2023
Volume 29
Issue 5
Pages: SP420-SP422

Recent FDA Actions: June 2023

FDA Approves Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma

The FDA has granted accelerated approval to enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.1 The regulatory decision was supported by data from the phase 1/2 KEYNOTE-869 study (NCT03288545).2

In dose-escalation cohort and cohorts A and K (n = 121), the doublet regimen elicited a confirmed objective response rate (ORR) of 68% (95% CI, 59%-76%) by RECIST v1.1 criteria and blinded independent central review (BICR). Among those who responded, 12% achieved a complete response and 55% had a partial response.

Moreover, the median duration of response (DOR) in the dose-escalation cohort plus cohort A was 22.1 months (range, 1.0+ to 46.3+) and not yet reached (range, 1.2 to 24.1+) for cohort K.

“The accelerated approval for the combination of Padcev and pembrolizumab marks an important milestone for the approximately 8000 to 9000 patients in the United States with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy,” Ahsan Arozullah, MD, MPH, senior vice president and head of development therapeutic areas at Astellas Pharma, stated in a news release.3 “This patient population now has an additional treatment option to treat advanced bladder cancer at first diagnosis of metastatic disease.”

The open-label, multicohort study enrolled patients with locally advanced or metastatic urothelial cancer who were not eligible to receive cisplatin-based chemotherapy.4 Patients could not have received previous systemic therapy for locally advanced or metastatic disease. Other exclusion criteria included having active central nervous system metastases, having ongoing sensory or motor neuropathy that was at least grade 2 in severity, or having uncontrolled diabetes defined as hemoglobin A1C (HbA1C) of at least 8% or HbA1C of at least 7% with associated diabetes symptoms.

Those in the dose-escalation cohort (n = 5), cohort A (n = 40), and cohort K (n = 76) were administered enfortumab vedotin at 1.25 mg/kg intravenously over the course of 30 minutes on days 1 and 8 of each 21-day treatment cycle. This was followed by pembrolizumab, which was also given intravenously at 200 mg on day 1 of each cycle, approximately 30 minutes after enfortumab vedotin. Treatment continued until progressive disease or intolerable toxicity.

In the 121 patients, the median age was 71 years (range, 51-91); most patients were men (74%) and White (85%). Regarding ECOG performance status, 45% had a status of 1 and 15% had a status of 2. Moreover, just under half of patients (47%) had a documented HbA1C of less than 5.7% at baseline.

Reasons for being ineligible for cisplatin were baseline creatinine clearance of 30 mL/min to 59 mL/min (60%), ECOG performance status of 2 (10%), and grade 2 or higher hearing loss (13%). Sixteen percent of patients had more than 1 cisplatin-ineligibility criteria.

At baseline, 97.5% of patients had metastatic disease and 2.5% had locally advanced disease. Moreover, 37% of patients had upper tract disease and 84% had visceral metastasis at baseline, including 22% with liver metastases. Additionally, 39% of patients had transitional cell carcinoma (TCC) histology; 13% had TCC with squamous differentiation and 48% had TCC with other histologic variants. ORR and DOR by RECIST v1.1 criteria and BICR were the major efficacy outcome measures of the trial.

The median follow-up for combined dose-escalation cohort plus cohort A and cohort K was 44.7 months (range, 0.7-52.4) and 14.8 months (range, 0.6-26.2), respectively. The median treatment cycles received in these cohorts were 9 lines and 11 lines, respectively.

The most common toxicities with the regimen, occurring in more than 20% of patients, included increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, and increased lipase.1 Other adverse effects included decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.1

The clinical benefit of enfortumab vedotin plus pembrolizumab in patients with previously treated advanced urothelial cancer is being further evaluated in the phase 3 EV-302 trial (NCT04223856), which will serve as the confirmatory trial for the accelerated approval in the United States.3 Data from the study are also intended to serve as the basis for global registrations, according to the news release.

Global enrollment to the trial has been completed. The China extension of the study is enrolling participants. 

A version of this article first appeared on OncLive®.


  1. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed April 3, 2023.
  2. Hoimes CJ, Flaig TW, Miloswsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol. 2023;41(1):22-31. doi:10.1200/JCO.22.01643
  3. FDA grants approval for Padcev (enfortumab vedotin-ejfv) with Keytruda (pembrolizumab) for first-line treatment of locally advanced or metastatic urothelial cancer. News release. Seagen and Astellas Pharma. April 3, 2023. Accessed April 3, 2023.
  4. Enfortumab vedotin-ejfv. Prescribing information. Seagen Inc; 2023. Accessed April 3, 2023.

Pembrolizumab Receives Full Approval for Select Patients With MSI-H
or dMMR Solid Tumors

The FDA has granted full approval to pembrolizumab (Keytruda; Merck) for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors that have progressed following previous treatment and who have no satisfactory alternative options. Merck announced the approval in a statement on March 29, 2023.1

In 2017, pembrolizumab received accelerated approval as the first immunotherapy with a tumor-agnostic indication.2 The conversion to a regular approval was supported by findings from the multicenter, nonrandomized, open-label, multicohort, phase 2 KEYNOTE-158 (NCT02628067), KEYNOTE-164 (NCT02460198), and KEYNOTE-051 (NCT02332668) trials, with data from 504 adult and pediatric patients with over 30 kinds of cancer.

Data from a pooled analysis of the trials showed that at a median follow-up of 20.1 months (range, 0.1-71.4), pembrolizumab elicited an objective response rate (ORR) of 33.3% (95% CI, 29.2%-37.6%). The ORR comprised a 10.3% complete response rate and a 23.0% partial response rate.

More than half (77%) of those who responded to the agent (n = 168) experienced responses that lasted for at least 12 months; 39% responded for 36 months or longer. The median duration of response (DOR) was 63.2 months (range, 1.9+ to 63.9+).

The regulatory decision represents the first full approval for an immunotherapy agent based on a predictive biomarker, irrespective of solid cancer type, according to a press release issued by Merck.

“This approval reinforces the important role of Keytruda in certain patients with MSI-H or dMMR solid tumors facing a variety of cancers,” Luis A. Diaz Jr, MD, head of the Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, stated in a press release. “These data also further underscore the need for biomarker testing to identify patients who may be eligible for this therapy.”

A total of 124 patients with advanced MSI-H or dMMR colorectal cancer (CRC) that had progressed after fluoropyrimidine and oxaliplatin or irinotecan with or without a VEGF/EGFR monoclonal antibody–based therapy were enrolled in KEYNOTE-164. For KEYNOTE-158, 373 patients with advanced MSI-H or dMMR non-CRC whose disease had progressed after previous treatment were included. Notably, patients were prospectively enrolled with MSI-H or dMMR tumors to cohort K or retrospectively identified in 1 of 10 solid tumor cohorts (cohorts A-J). Lastly, the KEYNOTE-051 trial enrolled 7 pediatric patients with MSI-H or dMMR cancers.

MSI status was determined by utilizing local or central polymerase chain reaction testing, and MMR status was identified by local or central immunohistochemistry. Notably, none of the trials enrolled patients with autoimmune disease or a medical condition that needed to be treated with immunosuppressive drugs.

Adult participants were administered intravenous pembrolizumab at 200 mg every 3 weeks, and pediatric patients received the immunotherapy at 2 mg/kg every 3 weeks. Treatment continued until intolerable toxicity or progressive disease, or for up to 24 months.

For KEYNOTE-164 and KEYNOTE-158, investigators conducted tumor assessments every 9 weeks through the first year of treatment and then every 12 weeks thereafter. For KEYNOTE-051, tumor assessments were performed every 8 weeks for the duration of 24 weeks and every 12 weeks thereafter.

ORR served as the major efficacy outcome measure of the trials, as well as DOR per blinded independent central review and in accordance with RECIST 1.1 criteria.

In KEYNOTE-158, this was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. For KEYNOTE-051, these outcome measures were assessed by study investigators according to RECIST 1.1 criteria. 


  1. FDA converts to full approval indication for KEYTRUDA (pembrolizumab) for certain adult and pediatric patients with advanced microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. News release. Merck. March 29, 2023. Accessed March 29, 2023.
  2. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. Updated May 30, 2017. Accessed April 10, 2023.

FDA Approves Polatuzumab Vedotin Plus R-CHP for Previously Untreated DLBCL

On April 19, 2023, the FDA approved polatuzumab vedotin-piiq (Polivy) plus rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (R-CHP) for use in adult patients with previously untreated diffuse large
B-cell lymphoma (DLBCL), not otherwise specified (NOS) or high-grade B-cell lymphoma (HGBCL), and with an International Prognostic Index score of 2 or greater.1

The regulatory decision converts to a regular approval the June 2019 accelerated approval of the antibody-drug conjugate (ADC) in combination with bendamustine and rituximab (BR) for the treatment of patients with relapsed or refractory DLBCL who have previously received at least 2 therapies.2 FDA’s action was based on data from the phase 1b/2 GO29365 trial (NCT02257567), in which 40% of patients receiving the polatuzumab vedotin regimen achieved a complete response (CR) compared with 18% of patients in the BR-alone arm, meeting the primary end point of the study.

The frontline approval is supported by findings from the phase 3 POLARIX trial (NCT03274492), in which polatuzumab vedotin plus R-CHP (n = 440) significantly improved progression-free survival (PFS) compared with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; n = 439) in this patient population.3

The addition of the ADC to R-CHP resulted in a 27% reduction in the risk of disease progression, relapse, or death vs R-CHOP (HR, 0.73; 95% CI, 0.57-0.95; P < .02). Data presented at the 2022 Pan Pacific Lymphoma Conference showed that the 2-year PFS rate in the investigative arm was 76.7% (95% CI, 72.7%-80.8%) vs 70.2% in the control arm (95% CI, 65.8%-74.6%).

“It has been nearly 20 years since a new treatment option has become available to people [with a new diagnosis of] diffuse large B-cell lymphoma,” Levi Garraway, MD, PhD, executive vice president, head of global product development, and chief medical officer at Roche, stated in a news release.1 “[This] decision from the FDA to approve Polivy in combination with R-CHP in this setting brings a much-needed new treatment option which may improve outcomes and bring other benefits to many patients with this aggressive lymphoma.”

The international randomized, double-blind, placebo-controlled POLARIX trial enrolled patients with previously untreated LBCL, an International Prognostic Index score between 2 and 5 representing low-intermediate to high-risk disease, no central nervous system disease, and no primary mediastinal LBCL.4

The trial included patients with several types of LBCL, including DLBCL NOS, HBCL with MYC and BCL2 and/or BCL6 rearrangements, HGBL NOS, and other low-grade B-cell lymphomas. These include T-cell/histiocyte-rich LBCL, Epstein-Barr virus–positive DLBCL, ALK-positive LBCL, and HHV8-positive DLBCL.

Participants were randomly assigned 1:1 to receive either 1.8 mg/kg of polatuzumab vedotin once daily plus 375 mg/m2 of rituximab, 750 mg/m2 of cyclophosphamide, and 50 mg/m2 of doxorubicin for six 21-day cycles, or standard-of-care R-CHOP. All patients received 375 mg/m2 of rituximab daily for cycles 7 and 8.

Investigator-assessed PFS served as the trial’s primary end point. Key secondary end points comprised event-free survival (EFS), end-of-treatment PET-CT CR rate, disease-free survival (DFS), overall survival (OS), and safety.

Additional data showed that the hazard ratio for EFS with polatuzumab vedotin plus R-CHP vs R-CHOP was 0.75 (95% CI, 0.58-0.96; P = .02). No significant difference between PET-CR rate at end of treatment was observed (78.0% vs 74.0%; P = .16), although DFS data suggested that responses are more durable with the polatuzumab vedotin combination (HR, 0.70; 95% CI, 0.50-0.98).

No significant difference in OS was observed between the treatment arms (HR, 0.94; 95% CI, 0.65-1.37; P = .75). At a median follow-up of 39.7 months, the median OS was not reached in either arm. At 2 years, the OS rate was 88.7% in both arms.

The toxicity profile of polatuzumab vedotin plus R-CHP proved to be comparable to that of R-CHOP.1 Grade 3 or 4 adverse effects (AEs) were experienced by 57.7% of those in the investigative arm and 57.5% of those in the control arm; serious AEs occurred in 34.0% and 30.6% of patients, respectively. Moreover, grade 5 toxicities were reported in 3.0% of those in the ADC arm vs 2.3% of those in the placebo arm. Toxicities resulted in dose reductions for 9.2% of those who received polatuzumab vedotin and for 13.0% of those who did not.

The most commonly reported toxicities included peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. Lymphopenia and neutropenia were the most commonly experienced grade 3 or 4 AEs.

The frontline regulatory approval follows the FDA’s Oncologic Drugs Advisory Committee vote of 11 to 2 in March 2023 that data from POLARIX support a favorable benefit-risk profile for polatuzumab vedotin in this population.5

This article originally appeared on OncLive and has been lightly edited.


  1. [Ad hoc announcement pursuant to Art. 53 LR] FDA approves Roche’s Polivy in combination with R-CHP for people with certain types of previously untreated diffuse large B-cell lymphoma. News release. Roche. April 19, 2023. Accessed April 19, 2023.
  2. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA. June 10, 2019. Accessed April 19, 2023.
  3. Mehta-Shah N, Tilly H, Morschhauser F, et al. Polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL): results from the phase III POLARIX study. Poster presented at: 2022 Pan Pacific Lymphoma Conference; July 18-22, 2022; Koloa, HI.
  4. A study comparing the efficacy and safety of polatuzumab vedotin with rituximab-cyclophosphamide, doxorubicin, and prednisone (R-CHP) versus rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in participants with diffuse large B-cell lymphoma (POLARIX). Updated March 1, 2023. Accessed April 19, 2023.
  5. Oncologic Drugs Advisory Committee (ODAC) Meeting: March 9, 2023. FDA YouTube page. Accessed April 19, 2023.

Epcoritamab Approved by FDA to Treat R/R DLBCL

The FDA has approved the T-cell–engaging bispecific antibody epcoritamab-bysp for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including those with DLBCL arising from indolent lymphoma or high-grade B-cell lymphoma.

Epcoritamab, to be marketed as Epkinly, will be available to patients who have received 2 or more lines of systemic therapy. It was approved May 19 under the FDA’s accelerated approval pathway, which will require verification of clinical benefit in confirmatory trials. The therapy is being jointly developed by AbbVie and Genmab.

DLBCL is a fast-growing type of non-Hodgkin lymphoma (NHL) and the most common type of the disease; it accounts for 30,400 new cases in the United States and 150,000 worldwide each year. Many new drug combinations have been developed for patients with R/R DLBCL, but as noted in a statement from AbbVie, single-agent off-the-shelf treatments are less common.1

“DLBCL is an aggressive cancer type that can rapidly progress and resist treatment. The FDA approval of [epcoritamab] represents a new treatment mechanism of action for third-line DLBCL patients,” Thomas Hudson, MD, senior vice president of research and development and chief scientific officer at AbbVie, said in the statement.

He highlighted epcoritamab’s status as a “nonchemotherapy, single-agent treatment” for DLBCL.

“The approval is just the first step, with our partner Genmab, toward a shared goal of developing a core therapy for patients with B-cell malignances,” he noted.

Epcoritamab is an immunoglobulin G1 (IgG1) bispecific antibody created using Genmab’s proprietary DuoBody technology, which induces potent cytotoxic activity of both CD4+ and CD8+ T cells to trigger an immune response toward target cell types. The technology is engineered to simultaneously bind to CD3 on T cells and to CD20 on B cells while inducing the destruction of CD20+ cells. The therapy is also being studied in follicular lymphoma and in chronic lymphocytic leukemia with Richter syndrome.

“The approval of [epcoritamab] in the US is an incredibly important milestone for patients with relapsed or refractory DLBCL who are in need of a new, innovative treatment option administered subcutaneously,” said Jan van de Winkel, PhD, CEO of Genmab, in a statement.2

Approval was based on results from the phase 1/2 EPCORE NHL-1 clinical trial [NCT03625037], which included an expansion cohort of 148 patients with CD20+ DLBCL, including 86% with DLBCL not otherwise specified, 27% with DLBCL transformed from indolent lymphoma, and 14% with high-grade B-cell lymphoma. Treatment with epcoritamab resulted in an overall response rate of 61%, a complete response rate of 38%, and duration of response of 15.6 months in heavily pretreated patients with R/R DLBCL.

“Patients with DLBCL who relapse or are refractory to currently available therapies have limited options. Generally, the prognosis for these patients is poor and management of this aggressive disease can be challenging,” Tycel Phillips, MD, City of Hope associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, said in the statement from AbbVie.1

“Epcoritamab is a subcutaneous bispecific antibody that offers an additional treatment option for this patient population,” Phillips said. “With this approval, patients who are in need of additional therapy may have the opportunity to receive epcoritamab after failure to respond or relapse after 2 or more systemic therapies.”

The FDA will require a boxed warning for serious or life-threatening cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome. Warnings and precautions include infections, cytopenias, and embryo-fetal toxicity. The most common adverse reactions, affecting at least 20% of patients, were CRS, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. 


  1. Epkinly (epcoritamab-bysp) approved by US FDA as the first and only bispecific antibody to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). News release. PRNewswire. May 19, 2023. Accessed May 19, 2023.
  2. Epcoritamab-bysp approved by US Food and Drug Administration as the first and only bispecific antibody to treat adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). BusinessWire. May 19, 2023. Accessed May 19, 2023.
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