Dylann Cohn-Emery

Preliminary findings from a phase 1/2 trial demonstrated promising intracranial activity and central nervous system (CNS) penetration with adagrasib (MRTX849) in patients with 

G12C-mutated non–small cell lung cancer (NSCLC) and active, untreated CNS metastases, according to a presentation at the 2022 American Society of Clinical Oncology Annual Meeting.

In patients enrolled in the phase 1b portion of the KRYSTAL-1 trial (NCT03785249) who received adagrasib, the intracranial objective response rate (ORR) was 32%, and the median overall survival (OS) and intracranial duration of response (DOR) were not reached.

G12C-mutant NSCLC are common and are associated with a poor prognosis. Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with 

G12C-mutant NSCLC and active untreated CNS metastases,” Joshua K. Sabari, MD, from Perlmutter Cancer Center, New York University Langone Health, said in his presentation.

For patients with this type of mutated NSCLC, about 27% to 42% will have CNS metastases at diagnosis, with a 5-month median OS for patients with active and untreated CNS involvement. Targeted therapies that penetrate the CNS improve outcomes for patients with these types of complications. Adagrasib has previously shown clinical activity in treated, stable CNS metastases, and tumor regression in animal models.

Patients with advanced solid tumors and a 

G12C mutation were given adagrasib as monotherapy or combined with pembrolizumab (Keytruda), cetuximab (Erbitux), or afatinib (Gilotrif) on KRYSTAL-1, a phase 1/2 multiple expansion cohort trial. The data that were presented look at the phase 1b cohort of patients with NSCLC and active, untreated CNS metastases treated with 600 mg of oral adagrasib twice daily. Safety and clinical activity were evaluated for this portion of the trial, including systemic and intracranial ORR by blinded independent central review (BICR), OS, DOR, and progression-free survival (PFS).

There were 25 patients enrolled, although not all were evaluable for efficacy of adagrasib. The median age in this cohort was 66 years (range, 47-89), and 52% of patients were female. A majority of patients were white (84%), had ECOG performance status of 1 (72%), and were current or former smokers (96%). About half of patients had received 1 prior line of therapy (20%), and the rest had received 0 (12%), 2 (20%), or 3 or more (16%) lines of therapy. Target CNS lesions at baseline were observed in 19 patients of the 25 patients and non-target lesions in 18 of the patients.

Among the overall evaluable population (n = 19), the ORR was 32%; for patients with only non-target lesions (n = 4) and target lesions with or without non-target lesions (n = 15), it was 50% and 27%, respectively. The complete response rate was 16% in the overall group, 50% in the non-target lesion group, and 7% in the target lesion group. Partial responses were also seen in 16% overall and 20% in patients with target lesions, but not in any patients with only non-target lesions.

Fifty-three percent of patients in both the overall and target lesion groups had stable disease (SD), while 50% had SD in the non-target lesion group. Investigators observed progressive disease in 11% of patients overall, 13% with target lesions, and none with non-target lesions. The disease control rate (DCR) was 84%, 80%, and 100%, for patients in the overall, target lesion, and non-target lesion groups.

“[In] the waterfall plot for BICR, intracranial disease control was broad, with intracranial tumor shrinkage of any magnitude occurring in 80% of radiographically evaluable patients with target lesions. One additional patient demonstrated 100% regression in the target lesions, however, [the patient] was non-evaluable due to the scans being performed too early,” Sabari noted.

There were objective intracranial responses observed in 32% of all patients (95% CI, 12.6%-56.6%). The intracranial DCR was 84% (95% CI, 60.4%-96.6%). Fourteen of the 16 patients who responded had concordance between systemic and intracranial disease control. Additionally, the systemic ORR by RECIST v1.1 was 37% (95% CI, 16.3%-61.6%) and the systemic DCR was 79% (95% CI, 54.4%-93.9%).

At median follow-up of 6.6 months, the median OS had not been reached. The median intracranial PFS was 4.2 months (95% CI, 3.8-not estimable [NE]). The median intracranial DOR had also not been reached (95% CI, 4.1-NE). Of the responders, 83% were still on therapy at the data cutoff of December 31, 2021.

An average Kp, uu of 0.47 was seen in 2 patients who had cerebrospinal fluid collected, which exceeds the values for patients who have received tyrosine kinase inhibitors that have shown CNS penetration and antitumor activity in CNS metastases. “Of note, both patients had evidence of CNS regression in their lesions via imaging compared to baseline. [One patient also] demonstrated a decrease in the edema compared to baseline,” Sabari said.

According to the safety profile, grade 1 or 2 treatment-related adverse events (TRAEs) occurred in 60% of the 25 patients who were evaluable for toxicity. There were no grade 4 or 5 TRAEs observed with adagrasib monotherapy. The most frequent grade 3 TRAEs were vomiting in 12%, and diarrhea, alanine transferase, and dizziness in 8% of patients each. Dose reductions/interruptions due to TRAEs were needed for 48% of patients, and discontinuation was needed in 1 patient (4%). CNS-specific TRAEs occurred in 6 patients, 5 reporting dizziness and 1 reporting grade 1/2 aphasia and insomnia.

“Adagrasib is the first KRASG12C inhibitor to demonstrate clinical activity in patients with 

G12C-mutated NSCLC with both treated as well as active, untreated CNS metastases,” Sabari stated. “An expanded-access program is open and enrolling patients with 

G12C-mutant solid tumors, including patients with active and untreated CNS metastases.”

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

Articles

In patients enrolled in the phase 1b portion of the KRYSTAL-1 trial who received adagrasib, the intracranial objective response rate was 32%.

Adagrasib Penetrates CNS in Early Data of KRAS G12C+ NSCLC

Nivolumab (Opdivo) and ipilimumab (Yervoy) combined with chemotherapy demonstrated long-term overall survival (OS) benefit as first-line therapy in patients with metastatic non–small cell lung cancer (mNSCLC) at a minimum follow-up of 3 years, according to updated findings presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

For patients on the CheckMate 9LA study (NCT03215706), the 3-year OS rate with nivolumab/ipilimumab plus chemotherapy was 27% versus 19% with chemotherapy alone. Progression-free survival (PFS) and duration of response (DOR) benefits were sustained at 3 years with the combination. Additionally, outcomes were not affected by mutational status of 

in an exploratory analysis portion of the trial.

“We have previously shown that nivolumab plus ipilimumab plus 2 courses of chemotherapy significantly improve OS with no new safety signals as compared [with] chemotherapy alone in patients with mNSCLC,” Luis G. Paz-Ares, MD, PhD, head of the Medical Oncology Service and Clinical Trial and Translational Oncology Research Group at Hospital Universitario 12 de Octubre in Madrid, Spain, said in his presentation. “We continue to see a sustained improved survival for those patients.”

The CheckMate 9LA trial randomized adult patients with previously untreated stage IV or recurrent NSCLC 1:1 to nivolumab at 360 mg every 3 weeks, ipilimumab at 1 mg/kg every 6 weeks, and 2 cycles of chemotherapy every 3 weeks versus chemotherapy every 3 weeks for 4 cycles. Patients with nonsquamous disease on the chemotherapy-alone arm could also receive optional pemetrexed (Alimta) maintenance. The primary end point was OS, while secondary end points were PFS, objective response rate (ORR), and efficacy by PD-L1 expression, and the exploratory end point was efficacy by oncogenic driver mutation status.

At 36.1-month minimum follow-up, the median OS for patients receiving the combination therapy (n = 361) compared with those who received chemotherapy only (n = 358) was 15.8 months versus 11.0 months, respectively (HR, 0.74; 95% CI, 0.62-0.87). There was also OS benefit regardless of PD-L1 status. This trial also looked at outcomes based on PD-L1 expression of less than 1% (HR, 0.67; 95% CI, 0.51-0.88), 1% or more (HR, 0.74; 95% CI, 0.60-0.93), 1% to 49% (HR, 0.70; 95% CI, 0.53-0.93), and 50% or more (HR, 0.75; 95% CI, 0.53-1.07).

The median PFS for all randomized patients was 6.4 months in the nivolumab/ipilimumab arm and 5.3 months in the chemotherapy-alone arm at minimum follow-up of 35.2 months (HR, 0.70; 95% CI, 0.59-0.83). The ORR was 38% compared with 25%, respectively. There was a 12.4-month median DOR and a 3-year DOR rate of 23% with immunotherapy versus 5.6 months and 14% with chemotherapy, respectively.

For patients with PD-L1–negative disease, median PFS was 5.8 months for patients given nivolumab/ipilimumab plus chemotherapy (n = 135) compared with those given chemotherapy alone (n = 129) at 5.0 months (HR, 0.69; 95% CI, 0.52-0.91). Patients had a 32% and 20% ORR on the respective study arms. The median DOR was 17.5 months versus 4.3 months, and there was a 3-year DOR rate of 37% versus 0%.

Lastly, for patients with PD-L1 expression of 1% or more, median PFS was 6.9 months on the experimental arm (n = 204) and 4.7 months on the chemotherapy arm (n = 204; HR, 0.71; 95% CI, 0.57-0.88). A 42% ORR was observed for immunotherapy versus a 28% ORR for chemotherapy alone. The median DOR was 11.3 months compared with 5.6 months, respectively; the DOR rate at 3 years was similar, at 18% and 17%.

“Importantly, we didn't see a robust difference in benefit from the [CheckMate] 9LA regimen in patients depending on the mutational status,” said Paz-Ares. “The benefit [was] very consistent in patients with mutation in 

, and in patients with wild-type for those oncogenic drivers.”

Over two-thirds of patients (n = 492; 68%) on the trial had nonsquamous NSCLC, and among those patients, 313 (64%) had tissue evaluable for mutations. Thirty-nine percent of the evaluable patients had a 

 mutation. These baseline characteristics were consistent with other nonsquamous and all-randomized populations with evaluable tissue. The subgroup of patients with 

 mutations was small, therefore limiting data interpretation.

For patients on CheckMate 9LA, the safety profile was consistent with previous reports and no new safety signals were identified. Forty-eight percent of patients had grade 3 or 4 treatment-related adverse events (TRAEs) for those receiving immunotherapy and 38% among those receiving chemotherapy alone. Discontinuation due to any grade TRAEs occurred in 22% of those receiving immunotherapy and 9% of those receiving chemotherapy alone. For those receiving the immunotherapy combination, the median treatment duration was 6.1 months (range, 0-24.4) compared with 2.5 months (range, 0-46.1). Patients received a median of 9.0 doses of nivolumab (range, 1-36) and 4.0 doses of ipilimumab (range, 1-18). Of the patients on this arm, 93% received 2 cycles of chemotherapy.

Subsequent systemic therapy was given to 37% of all randomized patients on nivolumab/ipilimumab plus chemotherapy and 49% on chemotherapy only. Subsequent immunotherapy was received in 8% and 36% of patients, respectively, and subsequent platinum-doublet chemotherapy in 19% and 6%.

The median age on the trial was 65 years in both arms and 30% of patients were female. Many of the patients had an ECOG performance status of 1 (68%), and the rest had a performance status of 0 (32%). Most patients were current or former smokers. Bone metastases were present in 27% of patients who received the combination and 31% who received chemotherapy alone, liver metastases were present in 19% and 20%, and central nervous system metastases were present in 18% and 16%. PD-L1 expression of less than 1% was identified in about 40% of patients, 1% or more in about 60%, 1% to 49% in 38% and 32%, and 50% or more in 22% and 29%.

“This updated analysis further supports the use of nivolumab plus ipilimumab plus 2 courses of chemo[therapy] as first-line treatment options for patients with mNSCLC regardless histology or PD-L1 expression,” Paz-Ares concluded.

Paz-Ares LG, Ciuleanu T-E, Cobo-Dols M, et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non–small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA. 

2022;40(suppl 17):LBA9026. doi:10.1200/JCO.2022.40.17_suppl.LBA9026

Three-year follow-up of the CheckMate 9LA trial shows continued survival benefit to nivolumab/ipilimumab plus 2 cycles of chemotherapy in patients with metastatic non–small cell lung cancer. 

Durable Survival Benefit Shown With Frontline Nivolumab/Ipilimumab in mNSCLC

After over 5 years of follow-up, enzalutamide (Xtandi) showed continued overall survival (OS) benefit in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to updated survival data presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

In the 3-year update of the ENZAMET trial (NCT02446405), an international, cooperative group, phase 3 study comparing enzalutamide with the standard of care as first-line therapy in mHSPC, patients with low-volume disease and M1 high-volume disease had more benefit than other groups on the study in addition to the benefit seen in the overall cohort.

“ENZAMET adds to the body of knowledge from several other pivotal trials and now informs best practices for mHSPC,” Ian D. Davis, MBBS, PhD, FRACP, FAChPM, of the Eastern Health Clinical School at Monash University in Box Hill, Australia, said in his presentation.

Previously, patients with low-volume mHSPC did better than those with high-volume disease when testosterone suppression (TS) alone was used, and the same was true in patients with metachronous metastatic disease over synchronous disease. However, combination treatments have shown to be more beneficial than TS alone in varying prognostic groups.

Patients in the ENZAMET trial (n = 1125) were randomized 1:1 to arm A, the control arm consisting of TS plus a standard non-steroidal antiandrogen ([NSAA] bicalutamide, nilutamide, or flutamide), or enzalutamide at 160 mg per day plus TS in arm B. Both arms were evaluated every 12 weeks until progression. Stratification factors included high versus low volume of metastases and use of planned early docetaxel.

At the time of ENZAMET’s interim analysis, the primary end point of OS was met in the combined overall cohort (HR, 0.67; 95% CI, 0.52-0.86; 

 There was improvement favoring the triplet of enzalutamide, TS, and docetaxel for prostate-specific antigen (PSA) progression-free survival (PFS) and clinical PFS, which were secondary end points. The clinical benefit outweighed the additional toxicity seen with the addition of enzalutamide, according to patient-reported outcomes. “It was clear that longer follow-up would be required, including, where possible, investigation of differential effects in various prognostic subgroups,” Davis said.

After a median follow-up of 68 months, with a data cutoff date of January 19, 2022, the preplanned analysis point of 470 events was met (n = 476).

 Investigators assessed the effect of enzalutamide based on prognostic grouping and the use of docetaxel. The presence or absence of M1 disease at initial diagnosis and whether or not patients had high-volume disease upon study entry were the 2 binary factors for prognosis for the updated data.

The median OS in the combined cohort was not reached (NR) with enzalutamide versus 73.2 months (95% CI, 64.7-NR) in the control arm (HR, 0.70; 95% CI, 0.58-0.84; 

< .0001). The 5-year survival rate was 67% compared with 57% in arm B and arm A, respectively.

“OS is, of course, influenced by access to and use of subsequent therapy, as well as the study intervention,” Davis explained. “The major difference between the treatment groups for subsequent therapies was the much higher use of enzalutamide or abiraterone [Zytiga] beyond progression in the control group. At the time of the analysis, 76% of those who progressed in the control group were treated with enzalutamide or abiraterone after progression compared to 26% in the enzalutamide group. The survival benefits for enzalutamide were not due to lack of access to effective therapies in the control group.”

In the enzalutamide arm, there was a median of 57.8 months of treatment, for those who remained on treatment, versus 22.6 months on the NSAA arm. Approximately 48% of patients remained on enzalutamide in the experimental arm at 5 years versus 23% of the control arm.

When reviewing these data, other key considerations included that this trial was representative of multiple subgroups of patients, including synchronous and metachronous disease, high- and low-volume disease, and those who did and did not receive docetaxel. The use of docetaxel for study patients was dependent on investigator discretion and assessment of “chemofitness” or predicted benefit. Concurrent docetaxel was planned for up to 6 cycles in 45% of patients, and 108 patients were given 1 cycle of docetaxel and 62 received 2 cycles before randomization.

The OS outcomes by subgroup and other secondary end points were evaluated as exploratory analysis and not formal comparisons due to limited numbers and potential confounders, according to Davis. There were 503 patients who received docetaxel, 602 with high-volume disease, and 683 with synchronous M1 disease. “The message is that no major differences in the effect of enzalutamide were detectable according to baseline characteristics,” Davis stated.

The addition of enzalutamide improved OS for those who received docetaxel, though those who were given early docetaxel did not have as much benefit. Additionally, those who had low-volume mHSPC may have had greater relative benefit over those with high-volume disease, even though both groups benefited. Of note, 71% of patients with high-volume disease also received docetaxel compared with 37% in those with low-volume disease.

There were no significant differences in the percent of patients alive at 5 years for those receiving enzalutamide when looking at baseline characteristics of volume of disease, M1 timing, and docetaxel use. Patients who received concurrent docetaxel who had high volume of disease had a 54% 5-year OS rate with enzalutamide and 51% with NSAA, and those with low volume had a 78% and 67% 5-year OS rate, respectively. The 5-year OS rates were 81% and 66% for those with low-volume mHSPC who did not receive docetaxel with enzalutamide and NSAA treatment, respectively, and 57% and 47% for those with high volume.

NSAA alone had the worst outcomes in the synchronous and metachronous subgroups, regardless of high- or low-volume disease. Enzalutamide and enzalutamide plus docetaxel had similar results, although treatment with concurrent docetaxel most likely has poorer prognosis according to Davis.

Many patients have not had PSA progression and continued on the experimental arm beyond the initial analysis. Enzalutamide added benefit for PSA PFS in all subgroups evaluated.

“This planned analysis after 476 events with a median follow-up of 68 months confirms the benefits of enzalutamide when added to best-practice standard of care,” Davis said. The ENZAMET study strengths were the active control arm, concurrent use of docetaxel, the mix of prognostic groups, and the primary end point of OS. Limitations included that the use of docetaxel was not randomized, and the trial was not powered for formal analysis of the subgroups.

The long-term follow-up confirms the OS benefit of enzalutamide in patients with mHSPC, especially for those with low-volume disease. Across the subgroups, there were no significant differences found with enzalutamide; however, the exploratory analyses suggested additional benefit with the triplet.

“The exploratory analyses raised the hypothesis that the greatest benefit of this triplet therapy with TS plus enzalutamide plus docetaxel may be limited to those with the poorest prognosis disease, particularly synchronous and high-volume metastatic disease. Enzalutamide should be considered in all patients with metastatic disease and especially in those for whom docetaxel is considered unsuitable or unlikely to be beneficial,” Davis concluded.

1. Davis ID, Martin AJ, Zielinski RR, et al; ENZAMET investigators. Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2022;40(suppl 17):LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004

2. Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835

Enzalutamide showed continued overall survival benefit in patients with metastatic hormone-sensitive prostate cancer after over 5 years of follow-up.

Enzalutamide Demonstrates Long-term Overall Survival in mHSPC

Preclinical data demonstrated potential for using the first-in-class oral molecular glue BTX-1188 in patients with solid tumors or acute myeloid leukemia (AML) and greater sensitivity in MYC dependent/high disease and is now being investigated in phase 1 clinical trials, according to a poster presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

BTX-1188 could prevent systemic inflammatory dose-limiting toxicities that are usually attributed to pure GSPT1 (G1 to S phase transition 1) degradation due to its immunomodulatory properties from the IKZF1/3 (Ikaros/Aiolos) degradation. The FDA granted an Investigational New Drug Application for BTX-1188 and a phase 1 trial (NCT05144334) was initiated to assess the safety and toxicity profile, as well as the pharmacokinetics and preliminary activity, of the drug in hematologic and solid malignancies.

The translation termination factor GSPT1 and transcription factor IKZF1/3 are required for the development and differentiation of lymphocytes and the modulation of cytokines.

 “BTX-1188…degrades GSPT1 and Ikaros/Aiolos, or IKZF1 and IKZF3, thereby resulting in inhibition of protein translation and in modulation of cytokines, respectively,” Aparajita Hoskote Chourasia, PhD, said in her presentation.

For the preclinical study, investigators gave athymic or BALB/c nude mice xenograft models a vehicle or BTX-118. They measured cell viability in cells treated with BTX-118 and patient samples by CellTiter-Glo 2.0 assay. Immunoblots of protein lysates from cells treated with DMSO (dimethyl sulfoxide) or BTX-118 were used to analyze substrate degradation and apoptosis profiles. Interleukin (IL)-2 or lipopolysaccharide (LPS)-induced measurements of inflammatory cytokines upon DMSO or compound treatment were taken after human peripheral blood mononuclear cells (PBMCs) were stimulated with αCD3.

In addition to rapid and deep degradation of GSPT1 and IKZF1/3, BTX-1188 also an inhibitor of MYC in multiple cell lines. The AML cell line MV-4-11 showed significant GSPT1 and IKZF1/3 degradation after 2 hours of treatment with 100 nM of BTX-1188 (

< 1 × 10-5) and 6 hours with 3 nM (>90% of GSPT1), respectively, in a proteomics and immunoblot analysis. According to the study investigators, this indicates rapid and potent neosubstrate degradation.

“Our data show that it has single-digit nanomolar DC50 for the Cereblon neosubstrates both in AML and in lymphoma, and that it also significantly inhibits MYC at low nanomolar concentrations,” Chourasia explained.

The investigators also observed significantly lower levels of GSPT1 and sustained apoptosis after treatment with 30 nM for 6 hours followed by washout, similar to what has been seen with PARP cleavage for up to 24 hours. BTX-1188’s durability in degrading GSPT1 expresses as low nanomolar IC50 even though there was 72-hour period of compound washout.

Inhibition of proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α, and induction of IL-2 by LPS and αCD3-stimulated PBMCs demonstrates BTX-1188 immunomodulatory properties. “These immunomodulatory properties are expected to improve clinical outcomes and reduce toxicities associated with selective GSPT1 degradation [without IKZF1/3 degradation], thus expanding its therapeutic window,” Chourasia said.

For cancer cell lines such as primary human patient AML samples (IC50 range, 0.4-1.5 nM) and MYC-dependent and non-MYC dependent lines (IC50 range, 0.5-20 nM), BTX-1188 is functionally cytotoxic. This includes samples from disease that is relapsed/refractory, cytarabine resistant, or venetoclax (Venclexta) resistant.

efficacy models which received daily or intermittent dosing of BTX-1188 also showed durability of GSPT1 degradation and sustained apoptosis, further indicating significant and sustained antitumor activity.

“Based on this data, our drug has entered phase 1 clinical studies for both solid tumors, as well as AML,” Chourasia concluded.

The sequential dose-escalation study currently enrolling patients to investigate BTX-1188 is multicenter, open label, and nonrandomized. The approximately 168 eligible patients with either AML, advanced solid tumors, or non-Hodgkin lymphoma will receive 1 of 7 doses of BTX-1188. Evaluation of treatment-emergent adverse events and determination of the recommended phase 2 dose are the primary end points of the trial.

1. Chourasia AH, Majeski H, Pasis A, et al. BTX-1188, a first-in-class dual degrader of GSPT1 and IKZF1/3, for treatment of acute myeloid leukemia (AML) and solid tumors. J Clin Oncol. 2022;40(suppl 16):7025. doi:10.1200/JCO.2022.40.16_suppl.7025

2. BioTheryX receives IND clearance from FDA to proceed with phase 1 study of BTX-1188, a molecular glue, for the treatment of hematologic and solid malignancies. News release. PRNewswire. Published November 2, 2021. Accessed June 3, 2022. https://prn.to/3xee2F2

BTX-1188 could prevent systemic inflammatory dose-limiting toxicities that are usually attributed to pure GSPT1 degradation due to its immunomodulatory properties from the IKZF1/3 degradation. 

BTX-1188 Undergoing Evaluation in AML, Solid Tumors After Showing Promise in Preclinical Data

Patients with high-risk non–muscle invasive bladder cancer (HR-NMIBC) experienced benefit and a tolerable safety profile with the combination of tislelizumab plus nab-paclitaxel (Abraxane), regardless of PD-L1 expression, according to preliminary data presented at the 2022 American Urological Association Annual Meeting.

In TRUCE-02, an open-label, single-arm, phase 2 study (NCT04730232), there was a complete response (CR) rate of 62.5%, which met the primary end point of the trial. Additionally, the high-grade adverse events (AEs) rate was lower than 5% across the study participants.

Previously, the PEANUT trial (NCT03464734) investigating pembrolizumab (Keytruda) plus nab-paclitaxel showed a significant CR rate and low AE rate in the second-line treatment of patients with bladder cancer. The phase 2 KEYNOTE-057 trial (NCT02625961) also demonstrated efficacy and safety with pembrolizumab monotherapy as antitumor treatment in Bacille Calmette-Guérin–unresponsive patients with HR-NMIBC. Previously, tislelizumab showed efficacy in locally advanced or metastatic urothelial carcinoma, and TRUCE-02 investigators are seeking to confirm the benefit of tislelizumab plus nab-paclitaxel.

In this trial, patients with HR-NMIBC that cannot be completed resected received 3 or 4 cycles of tislelizumab on day 1 and nab-paclitaxel on day 2, both at 200 mg intravenously every 3 weeks followed by a multipoint resection biopsy. The primary end point is the patients’ CR rate, and secondary end points included cystectomy-free survival, duration of response, and the number and severity of AEs. The biospecimens of patients’ tumors were sent for analysis by AcornMed panel, which targets 808 cancer-related hotspot genes, before starting treatment. Immunohistochemistry staining was used to measure PD-L1 expression and whole-genome sequencing was used to evaluate urine sediments.

So far, 51 patients have been enrolled in the TRUCE-02 study; 32 patients have completed treatment of 3 or 4 cycles and met the primary end point. There were 20 patients of the 32 total who achieved CR, with a CR rate of 62.5%. Furthermore, 4 patients (12%) experienced a partial response (PR), and 5 (16%) had stable disease. Progressive disease was observed in 3 patients (9%). Currently, 4 patients (12.5%) have proceeded to cystectomy after treatment.

Positive PD-L1 expression was found in 12 (50%) out of the 24 patients who had response of either CR or PR. Three patients out of 8 (38%) who were unresponsive to treatment had positive PD-L1 expression. However, homologous recombination repair mutations may predict favorable prognosis, according to the investigators. The whole-genome sequencing results of patients’ tumor tissue and urine were considered uniform.

In patients receiving the tislelizumab combined with nab-paclitaxel, the most common low-grade treatment-related AEs included alopecia in 81% and fatigue in 34%. All other AEs were seen in 7% of patients or fewer. Immune-related severe AEs included cytokine release syndrome in 1 patient (3%) and 1 patient (3%) with popular and pustular rash.

The median age on the trial was 67 years (range, 44-85), and there were 25 male patients recruited. Patients had to have an ECOG performance status of 0 to 2. If patients had previously received PD-1, PD-L1, or CTLA-4 antibodies, or other immunotherapies previously, they could not be enrolled on the trial.

Hu H, Niu Y, Wang H, et al. Update of TRUCE-02: an open label, single-arm, phase 2 study of tilelizumab combined with nab-paclitaxel for high-risk non-muscle-invasive urothelial bladder carcinoma (HR-NMIBC) which is not completely resectable. Presented at: 2022 American Urological Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract MP59-19.

The combination of tislelizumab plus nab-paclitaxel demonstrated benefit and a tolerable safety profile in patients with high-risk non–muscle invasive bladder cancer.

Early Efficacy Seen With Tislelizumab/Nab-Paclitaxel in High-Risk NMIBC

Tislelizumab plus nab-paclitaxel (Abraxane) as neoadjuvant treatment demonstrated benefit with a high rate of pathologic complete response (pCR) in patients with muscle-invasive bladder cancer (MIBC), according to preliminary data presented at the 2022 American Urological Association Annual Meeting.

Investigators of the single-arm, open-label phase 2 TRUCE-01 trial (NCT04730219) did not observe an increase in adverse events (AEs) or a correlation of PD-L1 expression with the efficacy of the neoadjuvant therapy. However, high tumor mutation burden (TMB) did show a correlation to response with the combination.

Neoadjuvant treatment with immune checkpoint inhibitors showed comparable efficacy and fewer AEs than chemotherapy in the PURE-01 trial (NCT02736266) of pembrolizumab (Keytruda) and the ABACUS trial (NCT02662309) of atezolizumab (Tecentriq) in MIBC. Although, at this point, the efficacy of combination chemotherapy and PD-1/PD-L1 inhibition has not been determined. This study in patients with MIBC is evaluating the PD-1 inhibitor tislelizumab combined with second-line chemotherapy in the neoadjuvant setting.

In the ongoing TRUCE-01 trial, patients with stage T2-4aN0-1M0 disease were given 200 mg of tislelizumab on day 1 and 200 mg of nab-paclitaxel on day 2 every 3 weeks for 3 cycles, followed by complete transurethral resection of bladder tumor (cTURBT) or radical cystectomy. The Dako 22C3 pharmDx assay was used to conduct biomarker analysis on PD-L1 expression using combined positive score. TMB was also evaluated for the analysis. The primary end point was pCR, defined as the absence of a viable tumor (pT0N0M0).

Thirty patients completed this regimen of neoadjuvant tislelizumab plus nab-paclitaxel and received a radical cystectomy (n = 9) or cTURBT (n = 21) between July 2020 and July 2021. A total of 16 patients achieved pCR (53.3%; 95% CI, 36.7%-73.3%). Downstaging to pT less than 2 occurred in 21 patients (70%; 95% CI, 53.3%-86.7%), which was a secondary end point in this trial.

Patients who responded to therapy had a higher TMB level than those who did not respond (

 = .067). No significant correlation was observed between PD-L1 expression and the efficacy of the tislelizumab/nab-paclitaxel combination. Eight patients with PD-L1–positive expression achieved pT0 versus 8 patients with PD-L1–negative expression (

In terms of AEs, 1 patient experienced grade 3 rash and 1 patient had grade 4 acute renal failure. After corticosteroid treatment, both patients recovered. Alopecia was observed in 96% of patients, fatigue in 63%, hyperglycemia in 33%, rash in 27%, fever in 17%, and creatinine increase in 13% were the most common grade 1 or 2 AEs.

TRUCE-01 is currently enrolling adult patients with histopathologically confirmed urothelial carcinoma who are planning to receive a cTURBT or radical cystectomy. Patients must have an ECOG performance status of 0 to 2 and an expected survival over more than 12 weeks. Patients who have previously received a PD-1, PD-L1, or CTLA-4 antibody or other immunotherapies are not able to participate in this trial. The trial is located at Tianjin Medical University Second Hospital in Tianjin, China.

Hu H, Niu Y, Wang H, et al. Update of TRUCE-01: neoadjuvant tislelizumab combined with nab-paclitaxel for muscle-invasive urothelial bladder carcinoma. Presented at: 2022 American Urological Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract PD10-07.

Tislelizumab plus nab-paclitaxel as neoadjuvant treatment demonstrated benefit with a high rate of pathologic complete response in patients with muscle-invasive bladder cancer.