Megan Hollasch 

Patients with unresectable hepatocellular carcinoma (HCC) demonstrated favorable safety and efficacy signals when given envafolimab (KNO35) in combination with lenvatinib (Lenvima) and transarterial chemoembolization (TACE), according to findings from the phase 2 CISLC-12 study (NCT05213221) presented during the 2023 Gastrointestinal Cancers Symposium.

With a primary end point of objective response rate (ORR), results showed that patients (n = 36) achieved an ORR of 36.1% with 0 complete responses per RECIST 1.1 criteria. Outcomes assessed using modified RECIST (mRECIST) criteria showed an ORR of 77.8% with 1 complete response.

Investigators reported that 11 patients received radical resection after a conversion from envafolimab unresectable HCC to resectable disease.

“Envafolimab combined with lenvatinib plus TACE yielded favorable efficacy and safety outcomes, representing a promising therapeutic modality for patients with [Barcelona clinic liver cancer] BCLC B/C unresectable HCC,” wrote the authors in a poster of the data.

Patients enrolled had BCLC stage B (47.2%) or C (52.8%) unresectable HCC. Among 40 patients in the safety population, no treatment-related deaths occurred. The most common adverse events (AEs) were aspartate aminotransferase (AST) increase (75.0%), alanine transaminase (ALT) increase (65.0%), decreased white blood cell count (42.5%), gastrointestinal bleeding (42.5%), decreased platelet count (40.0%), increased blood thyroid stimulating hormone (37.5%), decreased neutrophil count (37.5%), and hypoalbuminemia (22.5%).

There was 1 grade 4 AE reported for each of the following events: increase in AST, increase in ALT, and gastrointestinal bleeding. Grade 3 AEs included increase in AST (n = 13), increase in ALT (n = 7), decrease in platelet count (n = 7), and decreased neutrophil count (n = 1).

Based on RECIST 1.1 and mRECIST, patients achieved a DCR of 77.8% vs 80.6%, a stable disease rate of 41.7% vs 2.8%. Progressive disease was reported in 19.4% vs 16.7% of patients using RECIST and mRECIST criteria, respectively. Survival data are not mature yet.

The agents were given for up to 2 years or until disease progression or unacceptable toxicity. Lenvatinib was given at 8 mg at day to patients under 60 kg and at 12 mg a day for patients 60 kg or more and envafolimab was given as a 300 mg subcutaneous injection once every 3 weeks. TACE occurred every 6 weeks based on the proportion of viable tumors according to investigators’ consideration and an imaging evaluation was conducted every 6 weeks.

 Secondary end points were disease control rate (DCR), duration of response, progression-free survival, overall survival, and safety.

The prospective, open-label, single-arm study performed at the First Affiliated Hospital at Zhejiang University in China enrolled patients from March 2022 to September 2022 and is actively recruiting. The median age of patients enrolled was 54.5 years (range, 18-75), 5.6% were metastatic, Child–Pugh scores were either 5 (94.4%) or 6 (5.6%), and patients had portal vein tumor thrombosis as well as hepatic vein tumor thrombus at rates of 36.1% and 5.6%, respectively. All patients had ECOG performance score of 0, at least 1 measurable lesion, and did not receive prior systemic chemotherapy.

As TACE is a standard treatment for patients with intermediate-stage HCC and lenvatinib has shown efficacy when combined with immune checkpoint inhibitors in the treatment of HCC, investigators continue to evaluate the combination of therapies with the anti–PD-L1 inhibitor envafolimab.

Previously, a retrospective controlled study showed that patients (n = 60) treated with lenvatinib and TACE achieved an ORR of 68.3% compared with 31.7% for patients who received TACE alone as assessed by mRECIST (

 < .001). The DCR was 93.3% vs 86.7%, 

.224), respectively, and the most common AEs with the combination treatment were decreased albumin (55.0%), hypertension (48.3%) and decreased platelet count (46.7%).

1. Chen Y, Huang X, Hu W, et al. Efficacy and safety of envafolimab plus lenvatinib combined with TACE in unresectable hepatocellular carcinoma: An open-label, single-arm, phase 2 study—the CISLD-12 study. 

. 2023;41(suppl 4):558. doi:10.1200/JCO.2023.41.3_suppl.558

2. Study on therapeutic effect of combination of envafolimab, Lenavatinib and TACE in advanced HCC patients (CISLD-12). ClinicalTrials.gov. Updated March 15, 2022. Accessed January 20, 2023. https://clinicaltrials.gov/ct2/show/NCT05213221

3. Fu Z, Li X, Zhong J, et al. Lenvatinib in combination with transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma (uHCC): a retrospective controlled study. 

. 2021;15(3):663-675. doi:10.1007/s12072-021-10184-9

Articles

Favorable safety and efficacy data were seen with envafolimab, lenvatinib and transarterial chemoembolization in patients with unresectable hepatocellular carcinoma.

Envafolimab, Lenvatinib, and TACE Elicits Promising Efficacy/Safety in Unresectable HCC

The chimeric antigen receptor (CAR)-T cell product, ciltacabtagene autoleucel (cilta-cel; Carvykti), has expanded options for patients with multiple myeloma. The therapy is FDA approvaed for adult patients with relapsed/refractory multiple myeloma after 4 or more lines of prior therapy in the United States, and has continued to display promising efficacy in patients with multiple myeloma following early relapse, according to updated findings from a cohort of the phase 2 CARTITUDE-2 trial (NCT04133636).

Prior to the approval of cilta-cel, effective treatment options for patients with multiple myeloma who experience a relapse post frontline therapy remained an unmet need.

Results from the study presented during the 2022 ASH Annual Meeting showed that patients in cohort B treated with cilta-cel (n = 19) achieved an overall response rate (ORR) of 100% (95% CI, 82.4%-100.0%). Twenty-one percent of patients achieved a complete response (CR), 68% experienced a stringent CR, and 11% had a very good partial response. Investigators noted that responses deepened at the longer follow-up with 90% (95% CI, 66.9%-98.7%) of patients achieving a CR or better. The median time to first response was 0.95 months (range, 0.9-9.7) while median time to best response was 5.09 months (range, 0.9-11.8).

The multicohort CARTITUDE-2 study evaluated cilta-cel in different multiple myeloma patient populations as well as earlier-line settings. Patients in cohort B had early relapse after therapy with a proteosome inhibitor and immunomodulary drug. This was defined as progression within 12 months after autologous stem cell transplant (ASCT) or from the start of anti-multiple myeloma therapy for patients who did not have a stem cell transplant. The median number of prior lines of therapy received in cohort B was 1 (range, 1-1) and 78.9% of patients previously received an ASCT.

With a cutoff of June 2022, the median follow-up of updated CARTITUDE-2 cohort B safety and efficacy data was 18.0 months (range, 5.2-26.3). Three deaths occurred due to progressive disease; 2 of these 3 patients had high-risk cytogenetic profiles and investigators noted that none had extramedullary disease.

Investigators highlighted that the persistence and expansion of the CAR-T cells was consistent with the data collected in the phase 1/2 CARTITUDE-1 trial (NCT03548207). “Peak expansion of CAR-T cells occurred on day 13 [range, 9.8-14.8] and median persistence was 76 days [range, 26.9-273.1]… [the] CD4/CD8 CAR-positive T ratio was stable around 1:1 post cilta-cel infusion,” study authors wrote.

Additional findings showed that the median duration of response (DOR), median progression-free survival, and median overall survival were all not yet reached. The 18-month PFS rate was 83% (95% CI, 55.9%-94.3%) and the 18-month OS rate was 83% (95% CI, 55.7%-94.2%).

The safety of cilta-cel was predictable as well as manageable and the most common any grade hematologic adverse effects (AEs) were neutropenia (95%), anemia (58%), thrombocytopenia (58%), lymphopenia (47%), and leukopenia (32%). These AEs were also reported as grade 3/4 in 90%, 47%, 26%, 47%, and 32% of patients, respectively.

Additionally, cytokine release syndrome (CRS) was a CAR-T-related AE that occurred in 84% of patients at any grade and at grade 3/4 in 5%, with a median time to onset of 8 days (range, 5-11) and a median duration of 3.5 days (range, 1-7). It was resolved in all cases and some patients were given tocilizumab (63%) and corticosteroids (21%).

Any grade neurotoxicity occurred in 26% (n = 5) of patients at any grade. One patient had grade 1 immune effector cell-associated neurotoxicity syndrome and1 patient had grade 3 or greater movement and neurocognitive treatment with emergent AEs that had not yet resolved at the data cutoff. Another patient with parkinsonism had grade 3 or greater CRS but achieved a CR and follow-up is ongoing.

The primary end point of CARTITUDE-2 was minimal residual disease (MRD) negativity at a 10-5 threshold assessed by next-generation sequencing/flow. Secondary end points included ORR, DOR, time to response, AEs, and severity of AEs.

Patients had a median age of 58 years (range, 44-67) and males were 73.7% of the patient population. Three patients (15.8%) had a refractory status of triple class, while 15 patients (78.9%) were refractory to their last line of therapy. The median time since initial diagnosis to enrollment was 1.15 years (range, 0.5-1.9) and 20% of patients had a high-risk cytogenetic profile with del17p. Fifteen patients had MRD-evaluable samples and 14 patients were MRD-negative at the determined threshold while 2 of the 3 patients with high-risk cytogenetics were MRD-negative. Additionally, outpatient administration of the agent is currently being explored and 1 patient was treated in the outpatient setting.

Investigators concluded that data on the safety profile and efficacy of cilta-cel in patients with multiple myeloma who experienced early treatment failure or clinical relapse support further exploration of the agent in earlier lines of therapy.

Van de Donk N, Agha M, Cohen AD, et al. Ciltacabtagene autoleucel (Cilta-cel), a BCMA-directed CAR-T cell therapy, in patients with multiple myeloma (MM) and early relapse after initial therapy: CARTITUDE-2 cohort B 18-month follow-up. 

. 2022;140(suppl 1):7536-7537. doi:10.1182/blood-2022-159169

Ciltacabtagene autoleucel continues to show promise for the treatment of relapsed or refractory multiple myeloma.

Cilta-Cel Shows Potential to Fill A Treatment Gap in Early-Line Multiple Myeloma

Treatment with zanubrutinib (Brukinsa) showed clinically meaningful benefit to a large majority of efficacy-evaluable patients with B-cell malignancies who were intolerant to acalabrutinib (Calquence), according to updated results from the ongoing phase 2 BGB-3111-215 trial presented during the 2022 ASH Annual Meeting.

Among 18 efficacy-evaluable patients, the disease control rate (DCR), defined as stable disease or better, was 94% (95% CI, 72.7%-99.9%). The overall response rate (ORR) was 61% (95% CI,35.7%-82.7%). The median time to best overall response and the median time to first overall response were both 3 months (range, 2.7-11.1).

Eligible patients in cohort 2 (n = 21) in BGB-3111-215 had been previously treated for 

, small lymphocytic leukemia (n = 2), mantle cell lymphoma (n = 1), marginal zone lymphoma (n = 2), andWaldenström macroglobulinemia (n = 3), and were intolerant to a prior BTK inhibitor. Patients in cohort 2 were intolerant to acalabrutinib and received zanubrutinib at a dose of 160 mg twice daily (67%) or 320 mg once a day (33%). Patients who were intolerant only to ibrutinib were enrolled to cohort 1 (n = 57) and were not included in this analysis.

Inclusion criteria for acalabrutinib intolerance that led to discontinuation of treatment was defined as: grade 1 or greater nonhematologic toxicity for more than 7 days or of any duration with over 3 recurrent episodes, grade 3 or higher nonhematologic toxicity for any duration, grade 3 neutropenia with fever or infection, grade 4 hematologic toxicity that was persistent until discontinuation of BTK inhibitor, inability to use acid-reducing or anticoagulant agents due to the BTK inhibitor, and resolution of a grade 2 or higher BTK inhibitor to grade 1 or below or baseline with resolution of grade 1 toxicities to 0 or baseline before beginning zanubrutinib treatment. Exclusion criteria solely included disease progression during the previous treatment with a BTK inhibitor.

The primary objective of the study was evaluating safety based on the recurrence and change in severity of AEs associated with acalabrutinib. Secondary objectives included ORR, DCR, progression-free survival, and patient-reported outcomes. Previous findings from the trial demonstrated that zanubrutinib was well tolerated in patients with B-cell malignancies who were intolerant to ibruntinib (Imbruvica) and/or acalabrutinib.

Safety results from the analysis demonstrated that in cohort 2,75% of acalabrutinib any grade adverse events (AEs) did not occur during zanubrutinib treatment and there were no acalabrutinib AEs that recurred at a high severity. Additionally, 67% of patients did not experience any recurrence of previously experienced AEs.

The cumulative exposure to acalabrutinib prior to discontinuation was 4.6 months, however 67% of patients did not experience a recurrence of prior acalabrutinib intolerance events after a median of 7.6 months of zanubrutnib treatment. When examining AE recurrence, 19% of patients experienced the same grade, 6% experienced a lower grade, and 75% of patients had no recurrence at all when treated with zanubrutnib.

With a median follow-up of 8.6 months (range, 0.1- 23.8), the median duration of zanubrutinib treatment was 7.6 months (range, 0.1-23.8). Most patients (81%) remain on the study with 76% remaining on treatment. Five (24%) patients discontinued treatment because of an AE (2), 1 because of disease progression), and 2 due to withdrawal by patient. One patient died from progressive disease.

Two of the patients that discontinued treatment experienced recurrence of a prior acalabrutinib intolerance event and 52% of patients had a dose interruption due an AE while 14% had an event that led to dose reduction. Out of 3 patients who experienced the same intolerance event with ibrutinib and acalabrutinib treatments, 2 did not have a recurrence on zanubrutinib and one patient had a lower grade recurrence.

When examining the kinase selectivity of zanubrutinib, ibrutinib, acalabrutinib, and acalabrutinib’s major metabolite (M27), zanubrutinib had the highest selectivity. Inhibition at rates of 50% of greater were recorded in 7, 17, 15, and 23 kinases, respectively, of the 370 tested. The treatment of B-cell malignancies with BTK inhibitors can be limited by AEs but the investigators noted that zanubrutinib was “designed to maximize BTK occupancy and minimize off-target kinase binding and associated AEs.”

Patients in cohort 2 had a median age of 73 years (range, 51-87) and had received a median of 2 (range, 1-6) prior BTK treatments. The prior BTK inhibitor therapies were ibrutinib monotherapy, ibrutinib combination therapy, acalabrutinib monotherapy, and acalabrutinib combination therapy with patients receiving the treatments at rates of 48%, 4.8%, 95%, 4.8% of the treatments, respectively. The median acalabrutinib exposure was 4.6 months (range, 0.2-26.9).

Investigators noted that there were no decreases in atrial fibrillation, anemia, or thrombocytopenia/platelet count following treatment. The most common AEs of any grade were fatigue (29%), diarrhea (24%), hypertension (24%), arthralgia (19%), cough (19%), myalgia (19%), and COVID-19 (14%). Nineteen percent of patients experienced a grade 3 or higher AE with 2 patients experiencing a decrease in neutrophil count, which was the only grade 3 or higher AE that occurred in more than 1 patient.

Shadman M, Flinn IW, Kingsley EC, et al. Zanubrutinib in acalabrutinib-intolerant patients (Pts) with B-cell malignancies. 

. 2022;140(suppl 1):3655-3657. doi:10.1182/blood-2022-159726

Clinical benefit has been achieved with zanubrutinib treatment in patients B-cell malignancies who were intolerant to acalabrutinib.

Zanubrutinib Benefits Acalabrutinib-Intolerant Patients With B-Cell Malignancies 

Fam-trastuzumab deruxtecan-nxki (Enhertu), both as monotherapy and in combination with pertuzumab (Perjeta), displayed encouraging efficacy with no new safety signals among patients with HER2-positive metastatic breast cancer (MBC), according to findings from the dose expansion part of the phase 1b/2 DESTINY-Breast07 (NCT04538742) presented during the 2022 San Antonio Breast Cancer Symposium.

With a median follow-up of 11 months, patients achieved an unconfirmed objective response rate (ORR) of 87.0% (80% CI, 73.2%-95.1%) and a confirmed ORR of 69.6% (80% CI, 54.1%-82.2%) in the monotherapy module (n = 23). Those who were assigned to the trastuzumab deruxtecan plus pertuzumab module (n = 22) had a median follow-up of 10 months and achieved an unconfirmed ORR of 81.8% (80% CI, 66.9%-91.8%) and a confirmed ORR of 72.7% (80% CI, 57.0%-85.0%). The median duration of treatment was 9.1 months (range, 0.7-13.2) and 9.2 months (range, 0.9-13.5).

In addition to exploring the safety and tolerability of trastuzumab deruxtecan as a monotherapy and in combination with pertuzumab, DESTINY-Breast07 is also evaluating combinations of trastuzumab deruxtecan with paclitaxel, durvalumab (Imfinzi), durvalumab plus paclitaxel, and tucatinib (Tukysa) in the randomized dose-expansion phase of the trial. Secondary end points included ORR, progression-free survival, time to second disease progression, duration of response, overall survival, pharmacokinetics, and antidrug antibodies to the agents in the study.

No grade 3 or higher nausea or vomiting adverse events (AEs) were reported and interstitial lung disease/pneumonitis was experienced by 1 patient with trastuzumab deruxtecan given as a single agent. One patient died from disease progression in the monotherapy module and 1 patient died from disease in the combination module.

The safety profiles of the agents were similar to those previously reported and all patients experienced any-grade AEs in the trastuzumab deruxtecan and trastuzumab deruxtecan plus pertuzumab groups. The most common for the groups, respectively, included the following: nausea (73.9% vs 63.6%), alopecia (47.8% vs 36.4%), vomiting (34.8% vs 40.9%), diarrhea (26.1% vs 63.6%), anemia (21.7% vs 36.4%), and COVID-19 infection (17.4% vs 40.9%). Grade 3 or higher events were reported in 30.4% of patients in the monotherapy module and the 40.9% in the combination module and serious AEs occurred in 8.7% and 13.6% of patients, respectively.

Another AE of interest was left ventricular dysfunction, which 2 patients in the monotherapy group experienced.

As part of the study methods, preclinical assessment using live cell imaging showed that when combined with pertuzumab, trastuzumab deruxtecan was internalized more rapidly and effectively. The authors also noted, “Trastuzumab deruxtecan combined with pertuzumab showed a greater reduction in total HER2 protein in cell lysate immunoblotting and enhanced internalization in 

 expressing cells than with either drug alone.”

Treatment remains ongoing for 73.9% of patients in the trastuzumab deruxtecan module and for 72.7% of patients in the trastuzumab deruxtecan plus pertuzumab module. Therapy was discontinued by 26.1% and 27.3% of patients, respectively for the following reasons: AEs (8.7% and 13.6%), objective disease progression (4.3% and 9.1%), withdrawal by patients (8.7%, 4.5%), and lost to follow-up (4.3% and 0%).

The median age in the study was 53.4 years (range, 34-80) in the monotherapy module and 53.2 years (range, 33-75) in the combination module. Most patients in the trastuzumab deruxtecan monotherapy and combination modules had a hormone receptor status of estrogen receptor (ER)–negative and progesterone receptor (PR)–negative (47.8% and 40.9%, respectively). Additionally, ER–positive and PR–negative (17.4% and 18.2%), ER–positive and PR–positive (34.8% and 36.4%), were reported. Additionally, one patient (4.5%) had a status of ER–negative and PR–positive in the combination module.

HER2-positive status as assessed by immunohistochemistry (IHC)was IHC 3+ among 73.9% of patients in the monotherapy module and 86.4% in the combination module. IHC 2+/in situ hybridization–positive in 21.7% and 9.1% of patients, respectively. One patient in each module had missing status.

Patients did not receive any lines of therapy for advanced or metastatic disease and did not have brain metastases or previously treated stable brain metastases. Patients received trastuzumab deruxtecan at a dose of 5.4 mg/kg every 3 weeks and pertuzumab was given at 420 mg every 3 weeks with a loading dose of 840 mg.

Investigators noted that these results supported the use of trastuzumab deruxtecan monotherapy as well as in combination with pertuzumab in larger trials such as the ongoing DESTINY-Breast09 (NCT04784715); however, as this trial is still ongoing and the follow-up duration was relatively short, the results may evolve further.

Hamilton EP, Jhaveri KL, Loi S, et al. Dose-expansion study of trastuzumab deruxtecan as monotherapy or combined with pertuzumab in patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer in DESTINY-Breast07 (DB-07). Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PD18-11.

In the phase 1b/2 DESTINY-Breast07 study, positive results were shown with trastuzumab deruxtecan, even without the addition of pertuzumab.

Megan Hollasch | Authors

Articles

Envafolimab, Lenvatinib, and TACE Elicits Promising Efficacy/Safety in Unresectable HCC

Cilta-Cel Shows Potential to Fill A Treatment Gap in Early-Line Multiple Myeloma

Zanubrutinib Benefits Acalabrutinib-Intolerant Patients With B-Cell Malignancies

Trastuzumab Deruxtecan +/– Pertuzumab Shows Early Safety/Efficacy in HER2+ mBC