Caroline Seymour

Patients with previously untreated locally advanced or metastatic urothelial carcinoma experienced favorable progression-free survival (PFS; the time a patient lives without their disease progressing or worsening), overall survival (OS; the time a patient lives after treatment regardless of disease status) and objective response rates (ORRs; patients whose disease responded partially or completely to treatment) when treated with Padcev (enfortumab vedotin-ejfv) and Keytruda (pembrolizumab) versus chemotherapy, according to findings from prespecified subgroup analyses of the phase 3 EV-302/KEYNOTE-A39 trial.

Primary results from the trial were first presented at the 2023 ESMO Congress. During the 2024 

, lead study author Dr. Michiel S. Van Der Heijden reported new data illustrating the benefit of the combination in previously unpresented subgroups.“

Patients with previously untreated advanced or metastatic urothelial carcinoma lived longer before their disease got worse, and lived longer overall when treated with a combination of Padcev and Keytruda compared to chemotherapy.

The benefits of the Padcev and Keytruda combination were consistent across various patient subgroups, including those with visceral metastases and lymph node–only disease. These findings suggest a potential new standard of care for this type of cancer.

The combination treatment demonstrated a longer overall survival in patients with visceral metastases compared to chemotherapy. Patients with lymph node–only disease had not reached median overall survival with the combination, indicating extended survival benefits.

Patients in all studied subgroups experienced superior response rates with the Padcev and Keytruda combination, exceeding 60% in all cases. The response rates were notably higher compared to those receiving chemotherapy.

The benefit of (Padcev) plus (Keytruda) in all prespecified subgroups was consistent with the overall patient population. These results further support (Padcev) plus (Keytruda) as a new standard of care in locally advanced or metastatic urothelial carcinoma,” Van Der Heijden, leader of the Michiel Van der Heijden Research Group at the Netherlands Cancer Institute, said in a presentation of the data.

These results showed that the PFS benefit with the combination in patients with visceral metastases (hazard ratio [HR; the chance of something occurring], 0.45) and those with lymph node–only disease (HR, 0.40) was consistent with that of the overall population (HR, 0.45).

Moreover, OS benefit was similar to that of the overall population (HR, 0.47), regardless of the presence (HR, 0.47) or absence (HR, 0.46) of visceral metastases.

In the visceral metastases group, the median OS was 25.6 months with the combination versus 13.6 months with chemotherapy. In the lymph node–only cohort, the median OS was not reached with the combination (meaning more than half of the patients in that cohort were still alive) versus 27.5 months with chemotherapy.

Food and Drug Administration (FDA) approved the combination

 for patients with locally advanced or metastatic urothelial cancer. The decision was based on primary results from the EV-302 trial, which enrolled patients with treatment-naive locally advanced or metastatic urothelial cancer with no contraindications to platinum, Padcev or Keytruda. Patients also had to have a glomerular filtration rate at or above 30 mL/min, an ECOG performance status of 0 to 2 (meaning patients are capable of self-care but their ability to carry out daily activities may be limited) and no prior exposure to a checkpoint inhibitor.

Patients were randomly assigned to the combination or up to six cycles of chemotherapy consisting of gemcitabine plus either cisplatin or carboplatin. Treatment in the investigational arm was continued until disease progression, clinical progression, unacceptable toxicity or patients completed 35 cycles of Keytruda. Notably, maintenance therapy was allowed if deemed appropriate by the investigator following the completion and/or discontinuation of platinum-containing therapy.

All patients were stratified by cisplatin eligibility (eligible versus ineligible), PD-L1 expression (low [combined positive score (CPS) of less than 10] versus high [CPS of 10 or greater]), liver metastases (present versus absent), age (younger than 65 versus 65 or older), region (North America vs Europe vs rest of world), sex (female versus male), race (White versus other), ECOG performance status at baseline (0 versus 1 to 2), metastases (visceral versus lymph node only), primary disease site of origin (upper tract versus lower tract) and renal function (normal versus mild versus moderate versus severe).

Previous findings from the primary analysis showed a PFS advantage with the combination in cisplatin-eligible (HR, 0.48) and ineligible (HR, 0.43), as well as PD-L1–high (HR, 0.42) and PD-L1–low (HR, 0.50) subgroups. Similar results were seen in patients with (HR, 0.53) and without (HR, 0.43) liver metastases.

Earlier findings also showed an OS advantage with the combination in cisplatin-eligible (HR, 0.53) and ineligible (HR, 0.43), as well as PD-L1–high (HR, 0.49) and PD-L1–low (HR, 0.44) subgroups. Additionally, the presence of liver metastases did not seem to affect the magnitude of OS benefit seen with the combination (with: HR, 0.47; without: HR, 0.47).

Additional findings from the current analysis showed that consistent with the primary analysis, which showed an ORR of 67.7% with the combination versus 44.4% with chemotherapy, patients in all prespecified subgroups experienced superior response rates with the combination, surpassing at least 60% in all cases.

In cisplatin-eligible patients, the ORR was 70.8% with the combination versus 53% with chemotherapy. In cisplatin-ineligible patients, the ORRs were 63.9% versus 34.9%. In the PD-L1–low subgroup, the ORRs were 63.3% versus 41%. In the PD-L1–high subgroup, the ORRs were 71.1% versus 46.6%. Patients with liver metastases experienced ORRs of 60% versus 41.4%. Patients without liver metastases had ORRs of 70% versus 45.3%. Regarding metastatic disease site, patients with visceral metastases experienced ORRs of 64.1% versus 39.6%. Patients with lymph node–only disease had ORRs of 77.5% versus 53.4%.

The toxicity profile of the doublet was found to be generally manageable. No new safety signals were observed. Grade 3 or greater (moderate to severe) side effects were reported in 55.9% of patients who received Padcev plus Keytruda versus 69.5% of those given chemotherapy.

The most common treatment-related side effects reported in the Padcev/Keytruda arm (440 patients) included peripheral sensory neuropathy (nerve damage; any grade, 50%; grade 3 or higher, 3.6%), pruritus (itching; 39.8%; 1.1%), alopecia (hair loss; 33.2%; 0.5%), maculopapular rash (32.7%; 7.7%), fatigue (29.3%; 3%), diarrhea (27.5%; 3.6%), decreased appetite (26.8%; 1.1%), nausea (20.2%; 1.1%), anemia (low red blood cells; 13.9%; 3.4%), neutropenia (low neutrophils, a type of white blood cell; 9.1%; 4.8%) and thrombocytopenia (low platelets; 3.4%; 0.5%).

In the Padcev/Keytruda arm, four treatment-related side effects led to death: asthenia (fatigue), diarrhea, immune-mediated lung disease and multiple organ dysfunction syndrome. In the chemotherapy arm, four treatment-related side effects resulted in death: febrile neutropenia (fever), myocardial infarction (heart attack), neutropenic sepsis (reaction to an infection) and sepsis.

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Patients with previously untreated locally advanced or metastatic urothelial carcinoma experienced favorable progression-free survival, overall survival and objective response rates  when treated with Padcev and Keytruda versus chemotherapy.

Survival Benefits with Keytruda and Padcev in Advanced Urothelial Cancer

Patients with unresectable hepatocellular carcinoma (HCC; liver cancer) tended to live longer without their disease getting worse when Imfinzi (durvalumab) and Avastin (bevacizumab) was added to transarterial chemoembolization (TACE), compared to those who received TACE alone, according to findings from the phase 3 EMRALD-1 clinical trial presented at the 2024 

Adding Imfinzi (durvalumab) and Avastin (bevacizumab) to the standard TACE therapy for liver cancer resulted in patients living longer without their disease progressing, compared to those receiving TACE alone.

The study suggests that the combination of Imfinzi and Avastin with TACE has the potential to set a new standard of care for patients with unresectable hepatocellular carcinoma eligible for embolization.

The addition of Imfinzi and Avastin did not introduce new safety concerns, and the side effects were consistent with the known profiles of these medications. Patients reported manageable side effects, and the study will continue to monitor overall survival and long-term outcomes.

At the final analysis of progression-free survival (PFS; the time patients live after treatment without their disease worsening), the median PFS was 15 months with Imfinzi and Avastin plus TACE (given to 204 patients) compared to 8.2 months with TACE alone (205 patients), resulting in a 23% reduction in the risk of progression or death with the two systemic therapies. The 12- and 18-month PFS rates were 55.5% and 43.1% with durvalumab and bevacizumab vs 39.8% and 28.3% with TACE alone, respectively. Similar PFS benefit was seen across most prespecified subgroups.

“(Imfinzi) plus (Avastin) in combination with TACE has the potential to set a new standard of care in unresectable HCC eligible for embolization,” Dr. Riccardo Lencioni, lead study author and professor in the Department of Surgery, Medical, Molecular, and Critical Area Pathology at Università di Pisa in Italy, said in a presentation of the data.

For more than two decades, TACE has been a standard treatment for patients with embolization-eligible unresectable HCC despite the commonality of disease progression within one year of therapy. Given the efficacy of checkpoint inhibitors and VEGF inhibitors in advanced HCC and the resulting proinflammatory tumor microenvironment and increased VEGF signaling following embolization, investigators hypothesized that the addition of Imfinzi and/or Avastin could lead to prolonged tumor response.

The double-blind, global, placebo-controlled phase 3 trial enrolled patients eligible for embolization with unresectable measurable HCC per modified RECIST criteria, Child-Pugh A to B7 liver function, an ECOG performance status of 0 or 1 (indicating that they could independently perform their daily tasks), and no evidence of disease outside of the liver.

Patients who were candidates for curative therapy with surgical resection, ablation or transplantation; those who received prior systemic therapy or TACE; and those with grade 3 or 4 portal vein thrombosis were excluded from enrollment.

Eligible patients (616) were randomly assigned to one of three groups: Imfinzi plus Avastin and TACE (arm B); Imfinzi plus TACE (arm A); or TACE alone (arm C). The protocol allowed investigator’s choice of conventional TACE or TACE with drug-eluting beads.

The primary end point was PFS for the Imfinzi, Avastin and TACE arm vs the TACE-alone arm. Secondary end points included PFS for durvalumab plus TACE vs TACE alone, overall survival (OS; time from treatment until death of any cause), objective response rate (ORR; percentage of patients whose disease shrunk or disappeared from treatment), time to progression (TTP), safety, and quality of life for Imfinzi, Avastin and TACE vs Imfinzi and TACE vs TACE alone.

Patients underwent imaging for tumor assessment at week 12 and every nine weeks thereafter.

Stratification factors included TACE modality (DEB-TACE vs cTACE), geographical region (Japan vs Asia vs other) and portal vein invasion (Vp1 or Vp2+ / -Vp1 vs none).

Demographic and baseline features were generally balanced across arms. Most patients in the Imfinzi and Avastin arm had BCLC stage B disease (57.4%) followed by stage A (25.0%) and stage C (17.2%). More than half of patients across arms A, B and C received cTACE (59.4%; 58.3%; 58.5%). Approximately half of patients received treatment in Asia (52.1%; 52.4%; 52.1%), and most patients did not have portal vein invasion (93.7%; 92.2%; 93.7%).

Across all three arms, most patients had received one or two TACE procedures. A total of 43.6%, 42.5%, 40.0% of patients in the Imfinzi and Avastin, Imfinzi and TACE-alone arms remain on study, respectively, and 14.0%, 13.0%, and 13.5% of whom continue to receive Imfinzi.

The data cutoff date for the final PFS analysis, presented here with an approximate target maturity of 72%, and the interim OS analysis, was Sept. 11, 2023. At the time of data cutoff, OS was not statistically significant.

Additional results showed that the median PFS with the addition of Imfinzi to TACE was 10 months vs 8.2 months with TACE alone, failing to meet the secondary end point for PFS. This means that the researchers could not confidently say that one of the two regimens was superior in this instance.

The median TTP was improved with the addition of Imfinzi and Avastin to TACE vs TACE alone but not with Imfinzi alone. The median TTP was 22 months with Imfinzi and Avastin vs 10 months with TACE alone. The median TTP was 11.5 months with Imfinzi vs 10 months with TACE alone.

Regarding responses, the ORR was 43.6% with Imfinzi and Avastin, 41% with Imfinzi, and 29.6% with TACE alone. Notably, complete responses across the three arms were rare, with partial responses representing 40.6%, 39.5% and 27.1% of responses in the Imfinzi/Avastin, Imfinzi and TACE-alone arms, respectively. Stable disease lasting at least 20 weeks occurred in 22.3%, 20.5% and 31.0% of patients, respectively.

The median duration of response was 22.1 months, 14.0 months and 16.4 months with Imfinzi and Avastin, Imfinzi, and TACE alone, respectively.

“The median time from the start of TACE to the first dose of the combination therapy was similar across the three arms (at approximately three months),” Lencioni said. “However, the duration of exposure was longer in the post-TACE period as well as across the total study in the (Imfinzi) and (Avastin) arm, consistent with the PFS in these patients.”

Regarding safety, no new signals were identified. Within the safety analysis sets of the Imfinzi and Avastin (154 patients), Imfinzi (232 patients) and TACE alone (200 patients) arms, 45.5%, 27.6%, and 23.0% of patients had grade 3/4 (moderate to severe) side effects. Side effects leading to discontinuation occurred in 24.7%, 12.1% and 7.0% of patients, respectively. Deaths occurred in the Imfinzi and Avastin, Imfinzi, and TACE alone arms, at rates of 24.7% (38 patients), 12.1% (28 patients) and 7.0% (14 patients), respectively.

Some of the most common treatment-side effects of any grade reported in the Imfinzi and Avastin arm included hypertension (27.3%), post-embolization syndrome (26.6%), hypothyroidism (22.7%), pruritus (21.4%), protein in the urine (21.4%) and constipation (18.8%). Grade 3/4 side effects in this arm included hypertension (5.8%), anemia (4.5%), acute kidney injury (3.9%), protein in the urine (3.9%), post-embolization syndrome (3.2%), hepatic encephalopathy (3.2%), ascites (2.6%), hyponatremia (2.6%), and esophageal varices hemorrhage (2.6%).

“The incidence of (side effects) was consistent with the duration of treatment exposure and the known safety profiles of (Imfinzi, Avastin) and TACE, and the incidence of maximum grade 3 or 4 (side effects) was low across all arms,” Lencioni stated.

The study remains blinded to investigators and participants and follow-up will continue for OS.

Adding Imfinzi and Avastin to transarterial chemoembolization led to a 23% reduction in the risk of progression or death in patients with liver cancer.

Imfinzi, Avastin, TACE May ‘Set a New Standard of Care’ in Liver Cancer

An all-oral regimen showed overall survival and relapse-free survival benefits in patients with acute promyelocytic leukemia. 

Treatment with an all-oral regimen of arsenic trioxide, all-trans retinoic acid (ATRA) and ascorbic acid (AAA) demonstrated benefits to patients with acute promyelocytic leukemia (APL), according to findings from a trial that were presented at the 

Specifically, the researchers noted that the three treatments led to three-year overall survival (percentage of patients who are still alive after a specific amount of time) and relapse-free survival (length of time after primary treatment when a patient lives without signs of cancer) rates of 97% in the patient population.

“Use of an entirely oral AAA-based induction in a risk-adapted strategy that mitigated chemotherapy was highly effective and safe in newly diagnosed APL of all risk categories and all ages,” lead study author Dr. Harinder Gill, Department of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, the University of Hong Kong in China, said in a press conference during the meeting.

According to the National Cancer Institute, ACP is a fast-growing subset of acute myeloid leukemia, which is when there are too many immature blood-forming cells in both the blood and bone marrow.

Researchers reported that remission rates over 90% are common with ATRA and intravenous arsenic trioxide plus chemotherapy or ATRA and chemotherapy. However, the rate of relapse falls between 5% and 10%, reaching as high as 20% with conventional ATRA and chemotherapy.

Despite the relatively high rate of long-term survival, early death remains an issue for patients globally without access to arsenic trioxide, most commonly in resource-constrained countries. Although chemotherapy is an integral part of treatment, there is a need to reduce chemotherapy to lessen the rate of short- and long-term toxicities.

As such, investigators evaluated the efficacy and safety of an all-oral AAA-induction regimen in a risk-adapted strategy with no chemotherapy and minimal chemotherapy in low-risk and high-risk patients with APL.

Between Jan. 1, 2018, and Sept. 30, 2023, 51 men and 74 women were enrolled. The median patient age was 49 years, although five patients were under the age of 18. Most patients (93 patients) were at standard risk and 32 patients were at high risk. Eight patients had early deaths (intracerebral hemorrhage, six patients; APL differentiation syndrome [APL-DS], two patients); these patients were treated off protocol with oral AAA.

Overall, 117 patients received oral AAA-based induction on protocol, 92 (78.6%) received AAA alone and 25 (21.4%) received AAA in combination with daunorubicin.

Molecular responses of the all-oral induction, consolidation, and maintenance regimen were also evaluated. At a median follow-up of 31 months, results showed that all patients on the oral regimen treated on protocol achieved complete response.

At the time of data censoring, 63 patients had completed two years of oral AAA maintenance. Regarding fatality, one relapse leading to death occurred from refractory APL and one death in CR1 occurred due to an unrelated cause.

Regarding safety, the most frequent non-blood toxicity was transaminitis (increased levels of certain liver enzymes in the blood; 49.6%) and headache (36%). Neither cardiotoxicity nor grade 3 or grade 4 hepatotoxicity (impairment of the liver function) related to oral arsenic trioxide occurred, nor did treatment discontinuations due to oral arsenic trioxide. Of note, no treatment-related deaths occurred.

Among patients who received AAA, APL-DS occurred in 68 patients after beginning AAA, all within the first 14 days, and all fully responsive to dexamethasone (a drug that reduces inflammation and lowers the body’s immune responses).

The regimen will be further evaluated in a multicenter setting in Asia, and a pivotal trial is planned.

Treatment with an all-oral regimen led to three-year overall survival and relapse-free survival rates of 97% in patients with acute promyelocytic leukemia, a subset of acute myeloid leukemia.

All-Oral Regimen Demonstrates Survival Benefits, Safety in AML Subset

Presurgical Opdivo and chemo led to promising pathologic complete response rates in early-stage breast cancer.

Neoadjuvant (administered before surgery) Opdivo (nivolumab) and non–anthracycline containing chemotherapy produced promising pathologic complete response (pCR; the disappearance of cancer) rates regardless of whether Opdivo was administered before or during treatment with carboplatin and paclitaxel in patients with stage 1 to 2B triple-negative breast cancer (TNBC), according to findings from the phase 2 BCT1902/IBCSG 61-20 Neo-N trial presented at the 

At a median follow-up of 12 months, the pCR rate in the Opdivo lead-in arm was 51% versus 55% with concurrent administration, for an overall pCR rate of 53%.

“pCR rates exceeding 50% support a 12-week neoadjuvant non-anthracycline chemotherapy regimen with (Opdivo) for stage 1/2 TNBC,” the study authors wrote in their presentation.

Neoadjuvant systemic therapy with checkpoint inhibition is a standard of care in the treatment of patients with stage 2/3 TNBC. However, not all patients need to receive all components of the phase 3 KEYNOTE-522 regimen. Notably, findings from the phase 2 GeparNuevo trial demonstrated higher pathologic complete response rates with an immunotherapy lead-in versus concurrent chemoimmunotherapy, at 61% versus 38%, respectively.

The belief that immune enriched tumors may derive greater benefit from immunotherapy coupled with the notion that pCR is associated with good prognosis led investigators to evaluate a de-escalated chemotherapy approach in patients with TNBC.

Eligible patients had primary stage 1, 2A or 2B TNBC. Patients were randomly assigned to receive 360 mg of Opdivo and carboplatin at area under the curve 5 on day 1 every three weeks for four cycles, plus 80 mg/m2 of paclitaxel on days 1, 8 and 15 every three weeks for four cycles. This was administered with (arm A, 53 patients) or without (arm B, 55 patients) a two-week lead-in of 240 mg of Opdivo. Patients in arm B received the Opdivo lead-in after completing the four cycles of chemoimmunotherapy. Fourteen to 28 days after the last dose of paclitaxel and Opdivo, respectively, patients proceeded to surgery.

The study enrolled 110 patients, 108 of whom were evaluable, across 14 centers between July 2020 and April 2022. In both arms, the majority of patients were 40 years of age or above. Most patients were pre/perimenopausal (53%; 55%), had stage 2/3 disease (66%; 65%) and median Ki67 expression (70%; 70%). TIL (tumor-infiltrating lymphocyte) expression of at least 30% was present in 34% of patients in the lead-in arm and 33% of those in the concurrent arm; PD-L1 positivity was present in 43% and 51% of tumors, respectively.

Additional findings indicated that high TIL expression was the only predictor of pCR in a multivariable logistic regression model that accounted for age, study cohort, stage and TILs. pCR rates in patients with high TILs were 67% versus 46% in arms A and B, respectively.

“(The regimen) was well-tolerated, with no new safety signals seen,” the authors concluded.

EFS results are still maturing, and translational research is ongoing.

Opdivo and non–anthracycline containing chemotherapy before surgery produced promising pathologic complete response rates regardless of whether Opdivo was administered before or during treatment with carboplatin and paclitaxel in patients with stage 1 to 2B triple-negative breast cancer.

Caroline Seymour

Survival Benefits with Keytruda and Padcev in Advanced Urothelial Cancer

Imfinzi, Avastin, TACE May ‘Set a New Standard of Care’ in Liver Cancer

All-Oral Regimen Demonstrates Survival Benefits, Safety in AML Subset

Presurgical Opdivo, Chemo See High Response in Early-Stage Breast Cancer

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