The CD19-targeted CAR T-cell therapy rapcabtagene autoleucel (YTB323) was found to be well tolerated and to yield durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who had undergone 2 or more prior lines of therapy, according to updated data from a phase 1 trial (NCT03960840) presented at the 2022 ASH Annual Meeting.

Rates of complete response (CR) varied from 67% to 75% across the 4 dosage levels tested. Most patients received dose level 2 (n = 30) of 12.5 × 106 CAR-positive cells, and, among these, the CR rate was 73% (n = 22), with a further 10% (n = 3) achieving a partial response for an overall response rate (ORR) of 83% (95% CI, 65.3%-94.4%).

“Despite novel treatment options, a substantial portion of patients with [this disease] do not achieve sustained remission or do not have timely access to these therapies,” said lead study author Pere Barba, MD, PhD, member of the Hematology Department at Hospital Universitario Vall d’Hebron and the Vall d’Hebron Institute of Oncology in Barcelona, Spain. “There remains an unmet need to further improve response rates, durability of response, safety, and accessibility to patients.”

The CR rates at 6 months and 1 year among patients who received dose level 2 were 62% and 50%, respectively, after a median follow-up of 16 months (range, 4.4-27.5 months). The median duration of response was 16 months (95% CI, 10.4-not estimable [NE]).

Barba also reported on findings regarding cell kinetics during the presentation. “At a 25-fold lower dose, rapcabtagene autoleucel expansion at dose level 2, measured by qPCR [quantitative polymerase chain reaction], was at the higher end of tisagenlecleucel expansion in lymphoma,” said Barba. “We did not observe an increase in expansion or persistence at dose level 3 or dose level 4 compared with dose level 2.”

In total, 47 patients with DLBCL received rapcabtagene autoleucel. The median age of the examined population was 65 years (range, 35-79) and a slim majority of patients had an International Prognostic Index (IPI) score smaller than 3 (n = 25; 53.2%) rather than 3 or larger (42.6%). Most patients (72.3%) had 2 prior lines of therapy, and most were either refractory to their last line of therapy (34.0%) or primary refractory (21.3%). More than 68% of patients required bridging therapy.

All patients experienced at least 1 adverse effect (AE), and the vast majority experienced an AE of grade 3 or higher (93% of those receiving dose level 2, 100% of those receiving any other dose levels). Two patients experienced dose-limiting toxicities, comprising grade 4 cytokine release syndrome (CRS) in one and grade 4 pancytopenia lasting more than 28 days post-infusion in the other. Most other instances of CRS were grade 1/2, and this toxicity affected 25% to 37% of patients across the 4 dosage groups. There was a single case each of grade 3 and grade 4 CRS. “Notably, the time to onset of CRS was 8 days, which is somewhat later than what has been described with other similar therapies in lymphoma,” said Barba. There were 14 deaths in the cohort but none were related to the agent.

There were also 5 total instances of immune effector cell–associated neurotoxicity syndrome (ICANS), 2 of which were grade 3/4 among patients receiving dose level 2. “Again, the median time of onset (of ICANS events) was on day 16 after infusion, longer than has been described with other CAR T-cell therapies,” said Barba.

When asked, Barba indicated that toxicities from bridging therapy and other factors affected vein-to-vein time in this study. “A dose-escalation trial [such as ours] is probably not the best design to assess vein-to-vein time,” he said. “This will be [examined] in the expansion cohort…and will certainly be an end point for the next studies of YTB323.”

Based on the safety and efficacy data obtained, the investigators recommended the level 2 dose for further investigation in later-phase studies.

Barba P, Kwon M, Briones J, et al. YTB323 (rapcabtagene autoleucel) demonstrates durable efficacy and a manageable safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma: phase I study update. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana. Abstract 439.

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The CD19-targeted CAR T-cell therapy rapcabtagene autoleucel was found to be well tolerated and to yield durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma who had undergone 2 or more prior lines of therapy.

Rapcabtagene Autoleucel Induces Deep, Durable Responses in Relapsed/Refractory DLBCL

ARV-471 monotherapy elicited a significant clinical benefit rate (CBR) in patients with estrogen receptor (ER)–positive/HER2-negative locally advanced or metastatic breast cancer who had undergone prior hormonal therapy and chemotherapy, including those with 

 mutations, according to expansion cohort analysis from the phase 1/2 VERITAC trial (NCT04072952) presented by Anne F. Schott, MD, at the 2022 San Antonio Breast Cancer Symposium.

The phase 2, part B trial evaluated an expansion cohort who received 200 mg of ARV-471 orally, once a day (n = 35) or 500 mg of ARV-471 orally, once a day (n = 36). Enrollment in the 200-mg arm began before enrollment in the 500-mg arm.

The CBR for the 200-mg arm was 37.1% (95% CI, 21.5%-55.1%) and 38.9% (95% CI, 23.1%-56.5%) for the 500-mg arm. The CBR for all 71 patients was 38.0% (95% CI, 26.8%-50.3%).

 mutation, the CBR in the 200-mg arm (n = 19) was 47.4% (95% CI, 24.4%-71.1%) compared with 54.5% (95% CI, 32.2%-75.6%) in the 500-mg arm (n = 41). In this population, the total CBR was 51.2% (95% CI, 35.1%-67.1%).

In the phase 1 dose escalation trial presented previously at the 2021 San Antonio Breast Cancer Symposium,2 ARV-471 was well tolerated at all doses and the CBR was 40% (95% CI, 26%-56%) in 47 evaluable patients.

ARV-471 is a protein degrader, which causes degradation secondary to ER conformational changes or immobilization and differs from selective ER degraders such as fulvestrant (Faslodex).

“The mechanism of action of ARV-471 may provide more robust ER degradation, which may translate to stronger antitumor effects,” Schott, a professor of medicine at the University of Michigan Health and associate director of clinical research at the Rogel Cancer Center in Ann Arbor, Michigan, said in her presentation.1

The primary end point of the phase 2 trial was CBR and secondary end points included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Of the 71 patients who were enrolled, 69 were women, and the median age was 60 years (range, 41-86). The majority of patients had an ECOG performance status of 0 (66.2%) and 54.9% had visceral disease at enrollment.

At baseline, 57.7% of patients had mutant 

 and 35.2% had wild type. Overall, patients were heavily pretreated with a median of 3 prior lines of therapy in the metastatic setting. All patients received prior CDK4/6 inhibitor therapy per the inclusion criteria, 90.1% received prior aromatase inhibitors, and 78.9% were previously treated with fulvestrant. These characteristics were similar in both dosage groups.

Regarding safety, 3 patients in the 500-mg arm had adverse events (AEs) that necessitated a dose reduction to 400 mg but no patients required dose reduction in the 200-mg arm. One patient in the 200-mg arm and 2 patients in the 500-mg arm required dose discontinuation.

The majority of treatment related adverse events (TRAEs) were mild or moderate. Overall, 34% of patients had grade 1 TRAEs, 31% had grade 2 TRAEs, and 7% experienced grade 3/4 level TRAEs.

“The proportions of grade 1, 2, and 3 or higher TRAEs were similar in the 2 dosing groups,” Schott said. The most common TRAEs were fatigue, nausea, arthralgia, hot flushes, and increased aspartate aminotransferase (AST) levels. “Apart from one grade 3 fatigue event, all were grade 1 or 2,” said Schott.

Turning to the secondary end points, 1 patient in the 200-mg arm and 1 patient in the 500-mg arm had a confirmed partial response, according to Schott. “An additional 5 patients with target lesion reductions greater than 30% had unconfirmed partial responses, and therefore, their best response was reported as stable disease,” Schott said.

PFS was evaluated in the overall population and the 

-mutation positive population for both dose levels combined. The 500-mg arm, which started enrollment after the 200-mg arm, was not mature at the time of data cut off of June 6, 2022, and was not evaluated.

The preliminary median PFS was 3.5 months (95% CI, 1.8-7.8) in the 200-mg arm and 3.7 months (95% CI, 1.9-8.3) in the overall population. In patients with the 

 mutation, preliminary median PFS was 5.5 months (95% CI, 1.8-8.5) in the 200-mg arm and 5.7 months (95% CI, 3.6-9.4) in the total 

When reviewing ER degradation in the 200-mg arm, investigators reported a median degradation of 69% (range, 28%-95%) and a mean degradation of 71%, which is consistent with the mechanism of action of ARV-471.

“Based on the totality of the data, including comparable efficacy, favorable tolerability, and robust ER degradation, ARV-471 at 200 mg was selected as the phase 3 monotherapy dose,” Schott said. The phase 3 VERITAC-2 trial is planned to enroll 560 patients and will evaluate ARV-471 at 200 mg vs fulvestrant at 500 mg with a primary end point of PFS by blinded independent central review and secondary end points of OS, ORR, DOR, and CBR.

Hurvitz S, Ma C, Hamilton E, et al. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS3-03.

Hamilton E, Vahdat L, Han HS, et al. First-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2– locally advanced or metastatic breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium. Accessed December 8, 2022. https://bit.ly/3FDUgas

ARV-471 monotherapy elicited a significant clinical benefit rate in patients with estrogen receptor–positive/HER2-negative locally advanced or metastatic breast cancer who had undergone prior hormonal therapy and chemotherapy, including those with ESR1 mutations.

ARV-471 Monotherapy Demonstrates Clinical Benefit in ER+/HER2- Advanced Breast Cancer  

Concurrent adagrasib (MRTX849) and pembrolizumab (Keytruda) produced preliminary activity when administered as first-line treatment in patients with non–small cell lung cancer harboring a 

 G12C mutation, irrespective of PD-L1 status, according to data from the KRYSTAL-1 (NCT03785249) phase 1b and the KRYSTAL-7 (NCT04613596) phase 2 cohorts.

Data presented at the 2022 ESMO Immuno-Oncology Annual Congress showed that at a median follow-up of 3.5 months, the doublet elicited an objective response rate (ORR) of 49% (95% CI, 35%-63%) among the 53 clinically evaluable patients on KRYSTAL-7 who received at least 1 on-study scan. Of those who responded to treatment, 2% experienced a complete response and 47% experienced a partial response. Forty percent of patients achieved stable disease, and 11% experienced disease progression. The disease control rate (DCR) reported in this population was 89% (95% CI, 77%-96%).

Clinical activity with the regimen was observed across all PD-L1 subgroups. Specifically, responses were experienced by 59% of those with a PD-L1 tumor proportion score (TPS) of 50% or higher (n = 13/36), 48% of those with a score of 1% to 49% (n = 10/28), and 30% of those with a score of less than 1% (n = 3/11).

Moreover, at a median follow-up of 19.3 months, adagrasib plus pembrolizumab induced an ORR of 57% in evaluable patients enrolled to the phase 1b cohort of KRYSTAL-1, with a DCR of 100%. Responses occurred in both patients with a PD-L1 TPS of at least 50%, 1 of the 4 patients with a PD-L1 TPS of 1% to 49%, and in the 1 patient who had a PD-L1 TPS of less than 1%. All 4 responders experienced a durable response that persisted for longer than 9 months; 2 of these patients were still receiving the regimen for longer than 18 months.

“Initial results across all cohort suggest the concurrent combination of adagrasib and pembrolizumab may provide a chemotherapy-free option for treatment-naïve NSCLC with a manageable safety profile and encouraging clinical activity,” Pasi A. Jänne, MD, PhD, lead study author, senior physician, and director of the Lowe Center for Thoracic Oncology, the Belfer Center for Applied Cancer Science, and the Chen-Huang Center for EGFR Mutant Lung Cancers at the Dana-Farber Cancer Institute, Boston, MA, stated in a press release.

Approximately 14% of patients with NSCLC (adenocarcinoma) have tumors that harbor a 

 Adagrasib, a KRAS G12C inhibitor, was designed to have a half-life of 23 hours, a dose-dependent pharmacokinetic (PK) profile, and the ability to penetrate the central nervous system (CNS).

Prior data have demonstrated the activity of the agent in those with 

 G12C–mutated solid tumors, including those with NSCLC and CNS metastases.

 In preclinical models, investigators have observed a boost in immune response when adagrasib was paired with a PD-1 inhibitor.

Increased innate and adaptive immune responses have also been reported in patients who have received the KRAS G12C inhibitor.

The KRYSTAL-1 phase 1b and KRYSTAL-7 phase 2 cohorts included patients with 

G12C–mutated advanced, unresectable, or metastatic NSCLC who had not previously received systemic treatment for locally advanced or metastatic disease. Those with stable brain metastases were permitted.

In both studies, participants were given adagrasib at a twice-daily dose of 400 mg plus pembrolizumab at 200 mg every 3 weeks.

The primary end point of KRYSTAL-1 was safety, and secondary end points included ORR by RECIST v1.1 criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The KRYSTAL-7 phase 2 population included cohort 1a, those who had a PD-L1 TPS of less than 1%, and cohort 2, those with a PD-L1 TPS of 1% or higher. ORR by RECIST v1.1 criteria serves as the primary end point for KRYSTAL-7. Secondary end points comprise DOR, PFS, OS, safety, and PK.

Among the 75 patients enrolled to KRYSTAL-7, the median age was 66 years (range, 40-84); 51% of patients were female, 89% were White. Regarding ECOG performance status, 35% had a status of 0 and the remaining 65% had a status of 1. The majority (99%) were current or former smokers. Most patients had bone metastases at baseline (40%); 20% had liver metastases, 13% had adrenal metastases, and 12% had CNS metastases.

Additional data from this cohort showed that the median time to response to adagrasib plus pembrolizumab was 1.4 months. Of the 26 responders, 6 experienced a response after more than 2 months of treatment. Sixty-six percent of the 53 evaluable patients are still receiving the regimen, including in 24 patients with response.

Moreover, the doublet induced an ORR of 56% in a subset of response-evaluable patients who enrolled at least 6 months before the data cutoff date of August 30, 2022 (n = 14/25). Six of the 26 clinical responses happened at the time of the second on-study scan or later.

Regarding safety, 83% of the 75 patients in the KRYSTAL-7 cohort experienced an any-grade treatment-related adverse effect (TRAE); 15% had grade 1 TRAEs, 24% had grade 2 TRAEs, 40% had grade 3 TRAEs, and 4% had grade 4 TRAEs. No grade 5 TRAEs occurred.

The most common TRAEs experienced with the combination were nausea, diarrhea, vomiting, increased alanine (ALT) and aspartate (AST) aminotransferase, fatigue, decreased appetite, and increased amylase. The median time to onset for ALT and AST increase was 26 days and 37 days, respectively; only 1 patient reported new onset treatment-associated ALT/AST increase following 3 months.

Thirty-one percent and 41% of patients, respectively, experienced TRAEs that resulted in a dose reduction or interruption of adagrasib. Three percent of patients experienced TRAEs that led to discontinuation of both agents; 3% of patients experienced TRAEs that resulted in discontinuation of pembrolizumab alone.

“Based on these findings, phase 3 trials are planned in first-line NSCLC, evaluating concurrent adagrasib at 400 mg twice daily plus pembrolizumab vs standard of care by PD-L1 status,” Jänne, who is also a professor of medicine at Harvard Medical School, Boston, MA, concluded.

Jänne PA, Smit EF, de Marinis F, et al. Preliminary safety and efficacy of adagrasib with pembrolizumab in patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at: 2022 ESMO Immuno-Oncology Annual Meeting; December 7-9, 2022; Geneva, Switzerland. Presentation LBA4

Mirati Therapeutics presents late-breaking results evaluating concurrent adagrasib and pembrolizumab in first-line advanced/metastatic non-small cell lung cancer (NSCLC). News release. Mirati Therapeutics, Inc. December 5, 2022. Accessed December 7, 2022. 

Nassar AH, Adib E, Kwiatkowski DJ. Distribution of 

G12C somatic mutations across race, sex, and cancer type. 

. 2021;384(2):185-187. doi:10.1056/NEJMc2030638

Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. 

. 2020;10(1):54-71. doi:10.1158/2159-8290.CD-19-1167

Ou S-HI, Jänne PA, Leal TA, et al. First-in-phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced 

. 2022;40(23):2530-2538. doi:10.1200/JCO.21.02752

Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a 

. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619

Sabari JK, Spira AI, Heist RS, et al. Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial. 

. 2022;40(suppl 17):LBA9009. doi:10.1200/JCO.2022.40.17_suppl.LBA9009

Klempner SJ, Weiss J, Pelster M, et al. LBA24 KRYSTAL-1: updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation. 

. 2022;33(suppl 7):S1391. doi:10.1016/j.annonc.2022.08.020

Bekaii-Saab TS, Spira AI, Yaeger R, et al. KRYSTAL-1: updated activity and safety of adagrasib (MRTX849) in patients (pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a 

. 2022;40(suppl 4):519. doi:10.1200/JCO.2022.40.4_suppl.519

Briere DM, Li S, Calinisan A, et al. The KRASG12C inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. 

. 2021;20(6):975-985. doi:10.1158/1535-7163.MCT-20-0462

Concurrent adagrasib and pembrolizumab produced preliminary activity when administered as first-line treatment in patients with non–small cell lung cancer harboring a KRAS G12C mutation, irrespective of PD-L1 status, according to data from the KRYSTAL-1 phase 1b and the KRYSTAL-7 phase 2 cohorts.

Pipeline Report: December 2022

Articles

Rapcabtagene Autoleucel Induces Deep, Durable Responses in Relapsed/Refractory DLBCL

ARV-471 Monotherapy Demonstrates Clinical Benefit in ER+/HER2- Advanced Breast Cancer