Kristie L. Kahl

The combination use of tiragolumab plus atezolizumab (Tecentriq) demonstrated preliminary antitumor activity with an acceptable safety profile in heavily pretreated patients with metastatic esophageal cancer who were not previously treated with immunotherapy, according to data from a phase 1b dose-escalation and -expansion study (GO30103; NCT02794571) presented at European Society of Medical Oncology World Congress on Gastrointestinal Cancer 2021.

“Tiragolumab plus atezolizumab is well tolerated in patients with metastatic esophageal cancer, with expected treatment related adverse events [AEs] including immune mediated events that were mainly rash and laboratory abnormalities,” Zev A. Wainberg, MD, professor of medicine at UCLA and co-director of the UCLA GI Oncology Program, said during a presentation at the virtual meeting.

“The combination showed promising preliminary anti-tumor activity in patients with heavily pretreated esophageal cancer, who had not received immunotherapy, and durable responses were seen as a consequence and based in large part on this study. Tiragolumab plus atezolizumab is now being [evaluated in] large randomized phase 3 trials.”

In the phase 1b expansion cohort, AEs occurred in all patients (n = 21), including 67% who were grade 3 to 4 (n = 14). Serious AEs occurred in 71% of patients (n = 15), 8 patients had an AE that led to treatment interruption and 1 patient had to discontinue treatment.

Treatment-related AEs (TRAEs) occurred in 14 patients (67%), with 1 event being grade 3 (5%). In addition, immune-mediated AEs (imAEs) occurred in 12 patients (57%), with 3 events being grade 3 (14%). No Grade 4 or 5 TRAEs or imAEs were observed.

The most common AEs associated with the combination regimen, occurring in 10% or more of patients, were anemia (24%); decreased appetite, cough, aspartate aminotransferase increase, amylase increase (all 19%); as well as dysphagia, pyrexia, pruritis, rash, and alanine aminotransferase increase (all 14%). The most common imAEs were rash (38%), hepatitis (24%), pancreatitis (19%), as well as diabetes, hyperthyroidism, hypophysitis, and hypothyroidism (all 5%).

Of 18 evaluable patients with at least one tumor assessment, the objective response rate (ORR) was 28%, which includes 5 partial responses. The disease control rate was 50%, with 1 patient still in the study at 2-plus years.

“The responses included patients who had both adenocarcinoma and squamous cell histologies, with 1 patient having a complete resolution of all target disease that was squamous cell,” Wainberg said. “However, as you can see, we listed the prior lines of therapy demonstrating the majority of the responders were seen in heavily pretreated patients, and their response rates were present regardless of PD-L1 status in some of the patients who had very low expression of PD-L1 under 5%. Some of the best responses we’re seeing with this combination, but certainly patients who were also PD-L1 greater than 5%, as defined using the Ventana assay, did have some durable responses as well.”

The median progression-free survival (PFS) was 3.5 months (95% CI, 1.2-5.6), whereas the median duration of response was 15.3 months (95% CI, 7.0 to not reached).

Twenty patients have discontinued treatment, with the majority being a result of disease progression (71%), Wainberg noted.

TIGIT, or T-cell Immunoreceptor with Ig and ITIM domains, is a novel inhibitory immune checkpoint present on activated T cells and NK cells in multiple cancers. Moreover, its expression is correlated with PD-1, especially in tumor-infiltrating T cells, Wainberg explained.

Tiragolumab is a fully human IgG1/kappa monoclonal antibody that binds TIGIT to prevent its interaction with its ligand PVR.

“Anti-TIGIT antibodies, such as tiragolumab, could restore the anti-tumor response and may amplify the activity of anti–PD-L1/PD-1 antibodies,” Wainberg said.

In the phase 1b portion of the study, tiragolumab in combination with atezolizumab appeared to be tolerable, with clinical activity seen in an expansion cohort of patients with PD-L1-positive non–small cell lung cancer (NSCLC; ORR, 46%).

Patients – who were enrolled across the United States, Europe, and Asia – received tiragolumab 400 mg or 600 mg intravenously (IV) every 3 weeks plus atezolizumab 1200 mg IV every 3 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. The recommended phase 2 dose was tiragolumab 600 mg.

The randomized phase 2 CITYSCAPE trial (NCT03563716), designed to evaluate the combination as the frontline treatment of patients with metastatic, PD-L1-positive NSCLC, improved ORR (37% vs 21%, respectively) and PFS (5.5 months [95% CI, 4.21-10.4] vs 3.88 months [95% CI, 2.73-4.53]; stratified HR, 0.58; 95% CI, 0.38-0.89), compared with placebo plus atezolizumab.

“As it would seem natural, it seems inclined to investigate anti-TIGIT antibodies, in tiragolumab in particular, in other malignancies where PD-1 inhibition has been shown to be clinically validated,” Wainberg said. “This includes esophageal cancer, where the disease often occurs even after patients receive chemotherapy and targeted antibody immunotherapies. And in fact, TIGIT expression has been shown to be co-expressed with PD-1 in samples of esophageal cancer patients.”

Therefore, the researchers conducted a phase 1b expansion cohort. To be eligible, patients had to have metastatic esophageal cancer that had progressed on available therapies, had an ECOG performance score of 0 or 1, and had not been treated previously with cancer immunotherapy.

As of the data cut-off on April 8, 2021, 21 patients with metastatic esophageal cancer were treated with tiragolumab plus atezolizumab. Patients were a median age of 62 years (range, 50-77). In addition, the majority were male (86%) and White (43%). Overall, 76% had an ECOG performance score of 1, 38% of patients has 2 lines of prior therapies, 62% had squamous cell disease, and 24% had a PD-L1 status.

The combination regimen is now being evaluated further in 2 ongoing, randomized phase 3 studies: SKYSCRAPER-07 (NCT04543617) and SKYSCRAPER-08 (NCT04540211).

Wainberg Z, Matos I, Delord J, et al. Phase Ib study of the anti-TIGIT antibody tiragolumab in combination with atezolizumab in patients with metastatic esophageal cancer. 

. 2021;32:3. doi:10.1016/j.annonc.2021.06.012

Articles

The combination regimen was well tolerated with promising preliminary anti-tumor activity in patients with heavily pretreated esophageal cancer, who had not received immunotherapy.

Tiragolumab-Atezolizumab Combo Shows Preliminary Clinical Activity in Metastatic Esophageal Cancer 

Treatment with avapritinib (Ayvakit) in Chinese patients with 

D842V-mutant gastrointestinal stromal tumors (GIST) revealed promising clinical benefit, according to a bridging study of the NAVIGATOR trial (NCT02508532) presented at ESMO World Congress on Gastrointestinal Cancer 2021.

“Avapritinib had moderate clinical activity in the third and later-line treatment of a Chinese patient with GIST, making it the potential new treatment option for the population,” explained Jian Li, MD, PhD, Beijing Cancer Hospital, Beijing, China, during a presentation of the results.

In the open-label, multicenter phase 1/2 trial designed to evaluate avapritinib in patients with unresectable or metastatic GIST, the median duration of treatment was 25.4 weeks.

D842V-mutant GIST, the overall response rate (ORR) was 75%, including 15 patients with a partial response (PR). Similarly, in the third- and fourth-line treatment subgroup, 9 (39%) patients had an objective response, with 1 (4%) complete response and 8 (35%) PRs. The researchers noted that most responders (13 and 7, respectively) remain in remission.

The median progression-free survival (PFS) was not reached. In particular, for the 

D842V-mutant and third- and fourth-line treatment subgroups, median PFS was not reached and 5.5 months, respectively.

Lastly, the researchers noted, avapritinib was rapidly absorbed, and the drug exposure increased proportionally with dose at the steady-state. “The mean T1/2 ranged from 30.9-42.2 hours, supporting once daily dosing,” they wrote.

Grade 3/4 treatment related adverse events (TRAEs) occurred in 41 patients, with the most common being anemia (32%). There were no treatment-related deaths.

Avapritinib – a potent, selective, small-molecule inhibitor that targets 

 activation loop mutants – was approved in the United States based on findings from the NAVIGATOR study. The agent has been approved in China to treat adult patients with unresectable or metastatic GIST harboring 

 D842V, as the first approve precision therapy for this patient population in China.

At the meeting, Li reported on updated safety and efficacy data from the CS3007-101/BLU-285-1105, which is a bridging registrational study of the NAVIGATOR trial in China.

In phase 1 of the study, researchers aimed to determine the recommended phase 2 dose – between 200 mg daily (n = 6) and 300 mg (n = 6), and to assess the safety and pharmacokinetic (PK) characteristics (N = 12). In phase 2, they evaluated the preliminary efficacy and further assessed safety and PK (N = 48) following treatment at the 300-mg dose. In addition, the phase 2 study evaluated subgroups of patients: those with 

D842V-mutant GIST (n = 20) and as a third- or fourth-line treatment in patients who progressed on or could not tolerate standard therapy (n = 28).

Median age was 63 years (range, 43-70). The majority of patients were male (n = 41), had an ECOG performance score of 1 (n = 45), stage IV disease (n = 58), and metastatic disease (n = 59).

As of July 31, 2020, 60 patients were treated with avapritinib, including 6 treated at 200 mg and 54 treated with 300 mg. Forty patients were still on treatment, whereas 10 patients discontinued treatment due to death, 9 from disease progression, and 1 due to AEs.

Li J, Cai S, Deng Y, et al. Updated safety, efficacy, and PK results from an open-label, multicenter, phase I/II study of avapritinib in Chinese patients with unresectable or metastatic gastrointestinal stromal tumors. 

. 2021;32(suppl 3). doi:10.1016/j.annonc.2021.05.036

Treatment with avapritinib in Chinese patients with PDGFRA D842V-mutant gastrointestinal stromal tumors revealed promising clinical benefit, according to a bridging study of the NAVIGATOR trial.

Avapritinib Shows Promise in Chinese Patient Population With PDGFRA D842V-Mutant GIST

Patients with unresectable hepatocellular carcinoma (uHCC) with Child-Pugh class B (CP-B) liver function experienced a similar tumor size reduction as their Child-Pugh class A (CP-A) counterparts, all treated with lenvatinib (Lenvima), according to a post-hoc analysis of the phase 3 REFLECT study (NCT01761266) presented at ESMO World Congress on Gastrointestinal Cancer 2021.

“The results of this post hoc analysis suggest that patients with uHCC whose liver function deteriorates to CP-B after initiation of therapy may continue to receive lenvatinib,” the researchers wrote.

Results from the randomized, multicenter phase 3 REFLECT study– which led to the FDA’s approval of the agent for the first-line treatment of patients with uHCC – showed a benefit from lenvatinib, compared with sorafenib (Nexavar), irrespective of baseline liver function, including albumin-bilirubin (ALBI) grade 1 or 2 and CP score of 5 or 6.

However, of note, the trial enrolled patients with CP class A (CP-A) liver function per the study inclusion criteria, but not CP-B specifically.

“In the absence of any initial enrollment of patients with CP-B liver function, we conducted a post hoc exploratory analysis of key efficacy and safety outcomes in patients from REFLECT whose liver function had deteriorated to CP-B versus those whose liver function remained CP-A within 8 weeks post-randomization.”

The post hoc analysis assessed overall response rate (ORR), and landmark analyses that began after week 8, including progression-free (PFS) and overall survival (OS), both in patients whose liver function had deteriorated to CP-B and in patients whose liver function remained CP-A within 8 weeks post-randomization. In addition, safety was evaluated from baseline and adjusted by treatment duration.

Among patients treated with lenvatinib in the CP-B (n = 60) and CP-A (n = 413) subgroups, the median percent changes in tumor size from baseline to week 8 were –16.2% (range, –100 to 25) and –15.9% (range, –100 to 187), respectively, compared with 1.7% (range, –36 to 64) and 0% (range, –100 to 106) in patients treated with sorafenib in the CP-B (n = 47) and CP-A (n = 427) subgroups.

In the lenvatinib group, the CP-B and CP-A subgroups demonstrated ORRs of 28.3% (95% CI, 16.9-39.7) and 42.9% (95% CI, 38.1-47.6), respectively. In particular, for the CP-B subgroup of the lenvatinib arm, there were 0 complete responses (CRs), 17 (28.3%) partial responses (PRs), 17 (28.3%) patients with stable disease (SD), 12 (20.0%) with progressive disease (PD), and 14 (23.3%) were not evaluable (NE), compared with 10 (2.4%) CRs, 167 (40.4%) PRs, 142 (34.4%) with SD, 67 (16.2%) with SD, and 27 (6.5%) NE for the CP-A subgroup.

In the sorafenib group, the CP-B and CP-A subgroups demonstrated ORRs of 8.5% (95% CI, 0.5-16.5) and 12.9% (95% CI, 9.7-16.1), respectively. In particular, for the CP-B subgroup of the sorafenib arm, there were 0 CRs, 4 (8.5%) PRs, 12 (25.5%) with SD, 23 (48.9%) with PD, and 8 (17.0%) NE, compared with 4 (0.9%) CRs, 51 (11.9%) PRs, 207 (48.5%) with SD, 129 (30.2%) with PD, and 36 (8.4%) NE.

After week 8, median OS was 6.8 months (95% CI, 2.6-10.3) and median PFS was 3.7 months (95% CI, 1.8-7.4) in lenvatinib-treated patients within the CP-B subgroup, compared with 13.3 months (95% CI, 11.6–16.1) and 6.5 months (95% CI, 5.6–7.4), respectively, in the CP-A subgroup. In the sorafenib-treated CP-B subgroup, median OS and PFS were 4.5 months (95% CI, 2.9–6.1) and 0.5 months (95% CI, 0.1–3.6), respectively, compared with 12.0 months (95% CI, 10.2–14.0) and 3.6 months (95% CI, 0.1–3.6) in the CP-A subgroup.

In the CP-B and CP-A subgroups treated with lenvatinib, the median duration of treatment was 3.2 months (range, 0.3-31.5) and 6.9 months (range, 0.0-35.0), respectively, compared with 1.9 months (range, 1.9 months (range, 0.2-22.4) and 3.7 months (range, 0.1—38.7) in the sorafenib-treated CP-B and CP-A subgroups.

The mean dose intensity of lenvatinib was 8.4 mg/day/patient (standard deviation [SD], 3.07) and 9.5 mg/day/patient (SD, 6.01) in the CP-B and CP-A subgroups, respectively, whereas the mean dose intensity of sorafenib was 653.2 mg/day/patient (SD, 165.75) and 664.8 mg/day/patient (SD, 174.23) in the CP-B and CP-A subgroups, respectively.

Among the CP-B and CP-A patients, rates for grade 3 or higher treatment-related adverse events (TRAEs) in the lenvatinib arm were 3.65% (n = 95) and 1.41% (n = 419), respectively, and 3.38% (n = 42) and 1.71% (n = 388), respectively, in the sorafenib arm.

In their conclusion, the researchers noted, “As this post hoc analysis is limited by its descriptive nature, the efficacy results cannot be compared between CP–B and CP–A subgroups,” adding that further investigation is warranted.

“Although the treatment landscape for patients with unresectable hepatocellular carcinoma (uHCC) has recently expanded, there remains an unmet need for effective treatment options in patients with Child–Pugh class B (CP-B) liver function. Such patients are rarely included in clinical trials,” the researchers wrote in their poster.

In the trial, patients with uHCC were randomly assigned 1:1 to receive lenvatinib – for which dosage was based bodyweight: 12 mg/day for those weighing ≥ 60 kg; 8 mg/day for those weighing < 60 kg) – or sorafenib 400 mg twice daily in 28-day cycles.

At baseline, patients whose liver function deteriorated to CP-B within 8 weeks in the lenvatinib and sorafenib arms, 73.3% and 61.7%, respectively, had an ALBI score of 2, and 60.0% and 44.7% had a CP score of 6. Similarly, among those whose liver function remained CP-A within 8 weeks in both arms, 73.1% and 75.4%, respectively, had an ALBI score of 1, and 83.5% and 78.5% had a CP score of 5.

In the prior analysis, treatment with lenvatinib demonstrated higher ORR, compared with sorafenib, in patients with a CP score of 5 (OR, 4.88; 95% CI, 3.37-7.08) and in those with a CP score of 6 (OR, 5.25; 95% CI, 2.32-11.85), as well as in patients classified as either ALBI grade 1 (OR, 5.48; 95% CI, 3.70-8.10) or ALBI grade 2 (OR, 5.37; 95% CI, 2.61-11.06).

Huynh J, Thet Cho M, Jae-Hoon Kim E, Ren M, Amaya-Chanaga C, Vogel A. Post hoc analysis in patients with unresectable hepatocellular carcinoma who progressed to Child–Pugh B liver function in the phase 3 REFLECT study of lenvatinib vs sorafenib. 

. 2021;32(suppl 3) doi:10.1016/j.annonc.2021.05.133

Patients with unresectable hepatocellular carcinoma with Child-Pugh class B liver function experienced a similar tumor size reduction as their Child-Pugh class A counterparts, all treated with lenvatinib, according to a post-hoc analysis of the phase 3 REFLECT study.

Post Hoc Analysis Suggests Lenvatinib Therapy May Continue in Patients with Unresectable HCC, Child–Pugh class Liver Function

Updated results from the phase 1/2 CARTITUDE-1 trial (NCT03548207) showed that responses to ciltacabtagene autoleucel (cilta-cel) were deep and durable in patients with relapsed or refractory multiple myeloma (MM). Data at a median follow-up of 18 months were presented at the 2021 European Hematology Association (EHA) Congress.

Overall response rate (ORR) was 97.9%, including a 94.8% very good partial response (VGPR) or better. Moreover, the stringent complete response (sCR) rate was 80.4% and the partial response rate (PR) was 3.1%.

The median time to first response was 1 month (range, 0.9–10.7), with a time to best response of 2.6 months (range, 0.9-15.2). The median time to complete response or better (≥CR) was 2.6 months (range, 0.9-15.2). Duration of response was 21.8 months (95% CI, 21.8–not estimable [NE]), and median duration of response had not been reached in patients with sCR. The investigators estimated that 73% of responders had not progressed or died at 12 months.

Moreover, response rates were comparable across subgroups (range, 95%–100%), including number of prior lines of therapy, refractoriness, extramedullary plasmacytomas, and cytogenetic risk.

Of the 61 evaluable patients for minimal residual disease (MRD), 91.8% achieved MRD negativity at the 10-5 threshold, including 89.4% with ≥CR, compared with 57.7% and 43.3% of all patients, respectively. Median time to MRD negativity at 10-5 was 1 month (range, 0.8-7.7).

Among all patients, the 18-month progression-free survival (PFS) rate was 66.0% (95% CI, 54.9%-75.0%), and 75.9% (95% CI, 63.6%-84.5%) in those with sCR. Median PFS among all patients was 22.8 month (95% CI, 22.8 to NE) and was not reached in those with sCR.

Lastly, the 18-month overall survival (OS) rate in all patients was 80.9% (95% CI, 71.4%-87.6%).

The investigators did not identify any new safety signals with longer follow-up.

Cytokine release syndrome (CRS) occurred in 92 patients, of which the majority (94.6%) were grade 1/2 in severity. The median time to onset of CRS was 7 days (range, 1-12); however, the events resolved in 91 patients (98.9%) within 14 days of onset.

In addition, there was no new incidence of neurotoxicity with longer follow-up, and no additional movement and neurocognitive treatment-emergent adverse events (TRAEs).

No patient discontinued therapy due to manufacturing failure, while 1 patient received retreatment with cilta-cel.

In total, 21 patients died during the study, of which 10 were due to progressive disease, 6 from TRAEs as assessed by the study investigator, and 5 were from AEs unrelated to treatment.

Saad Z. Usmani, MD, FACP, director of the Plasma Cell Disorder Program and director of clinical research in hematologic malignancies at Atrium Health, noted during the meeting that new patient management strategies have been implemented in the trial to prevent and reduce the incidence of neurotoxicity, including enhanced bridging therapy to reduce tumor burden, early and aggressive treatment of CRS and immune effector cell–associated neurotoxicity syndrome, and handwriting assessments and extended monitoring.

“Patient management strategies to prevent or reduce these AEs have been successfully implemented in new and ongoing cilta-cel studies,” the investigators wrote. “This is reliant on effective implementation of these patient management strategies.”

The study was designed to evaluate cilta-cel, a chimeric antigen receptor (CAR) T-cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, in patients with relapsed/refractory MM who have been heavily pretreated.

Patients received a single cilta-cel infusion with a target dose of 0.75 × 106 CAR-positive viable T cells/kg and a median dose of 0.71 × 106 CAR-positive viable T cells/kg (range, 0.5–1.0 × 106 CAR+ viable T cells/kg) 5 to 7 days after lymphodepletion with 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine daily for 3 days. Bridging therapy was permitted after apheresis.

The primary aims of the study were to evaluate safety, confirm the recommended phase 2 dose (RP2D), and evaluate efficacy.

Key eligibility criteria for patients included progressive MM per International Myeloma Working Group (IMWG) criteria; receipt of 3 or more prior therapies or double refractory disease to a proteasome inhibitor (PI) plus immunomodulatory drug (IMiD) and a PI, IMiD, and an anti-CD38 antibody therapy; measurable disease; and an ECOG performance status ≤1.

Of the 97 patients who received cilta-cel infusion, 76 were ongoing at the time of the data cut-off. In total, 73 patients received bridging therapy between apheresis and cilta-cel infusion.

The median time from receipt to release of product for cilta-cel was 29 days (range, 23-64).

Patients had a media age of 61 years (range, 43-78). The majority were male (58.8%). Patients had received a median of 6 prior lines of therapy (range, 3-18), with 87.6% who were triple-class refractory and 42.3% who were penta-drug refractory. Lastly, 99% of patients were refractory to their last line of therapy.

In a previous analysis at 12.4 months of follow-up, the ORR was 97%, with an sCR of 67%. In addition, 12-month PFS and OS were 77% and 89%, respectively.

Cilta-cel is being investigated in the ongoing phase 2 CARTITUDE-2 (NCT04133636) and phase 3 CARTITUDE-4 (NCT04181827) studies in earlier-line settings.

Usmani S, Berdeja J, Madduri D, et al. UPDATED CARTITUDE-1 RESULTS OF CILTACABTAGENE AUTOLEUCEL, A B-CELL MATURATION ANTIGEN–DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY, IN RELAPSED/REFRACTORY MULTIPLE MYELOMA. Presented at: 2021 European Hematology Association Annual Meeting; June 9-17, 2021; Virtual; Abstract EP964.

Updated results from the phase 1/2 CARTITUDE-1 trial showed that responses to ciltacabtagene autoleucel were deep and durable in patients with relapsed or refractory multiple myeloma. Data at a median follow-up of 18 months were presented at the 2021 European Hematology Association Congress.

Kristie L. Kahl | Authors

Articles

Tiragolumab-Atezolizumab Combo Shows Preliminary Clinical Activity in Metastatic Esophageal Cancer

Avapritinib Shows Promise in Chinese Patient Population With PDGFRA D842V-Mutant GIST

Post Hoc Analysis Suggests Lenvatinib Therapy May Continue in Patients with Unresectable HCC, Child–Pugh class Liver Function

Cilta-Cel Shows High Response Rate Even After Longer Follow-Up in R/R Multiple Myeloma