Patients with perivascular epithelioid sarcoma (PEComa) of gynecologic or peritoneal origin experienced rapid, durable responses when treated with nab-sirolimus (Fyarro; ABI-009), according to a subgroup analysis of the phase 2 AMPECT trial (NCT02494570) presented by Thomas Herzog, MD, at the 2024 SGO Annual Meeting on Women's Cancer.

An overall response rate (ORR) of 37.5% (95% CI, 15.2%-64.6%) among 16 female patients with malignant PEComa in uterine, ovarian, pelvic, and retroperitoneal sites, regardless of 

mutation status was observed, and all responses were confirmed partial responses (PRs). Moreover, the disease control rate (DCR) in the subgroup was 62.5%, and 4 of 16 patients (25%) experienced stable disease for at least 12 weeks.

This subgroup comprised over half of the evaluable study population, and the ORR from this analysis was similar to the 38.7% ORR observed in the overall population evaluation. Additionally, the DCR in the overall population was 71%. Among all patients with malignant PEComa, the median duration of response (DOR) was 39.7 months, and the median overall survival (OS) was 53.1 months.

Regarding safety, 100% of patients experienced treatment-related adverse events (TRAEs) of any grade, while 63% of patients had a TRAE of grade 3. The most common any-grade TRAEs were stomatitis (81%), fatigue (63%), edema (56%), maculopapular rash (56%), diarrhea (50%), and nausea (50%). Grade 3 TRAEs included stomatitis (25%), hyperglycemia (13%), hypokalemia (13%), increased amylase (6%), vomiting (6%), and diarrhea (6%). There were no grade 4 or 5 TRAEs observed. TRAEs led to dose delay in 63% of patients, dose reduction in 31%, and treatment discontinuation in 6%.

The primary end point of the AMPECT study was ORR by independent review, and secondary end points included DOR, DCR, and safety/tolerability. Patients were eligible for enrollment if they were 18 or older, had an ECOG performance status of 0 to 1, had histologically confirmed malignant PEComa, had locally advanced or inoperable metastatic disease, and had not received treatment with a prior mTOR inhibitor.

A total of 16 female patients were evaluated in this subgroup analysis. The median age was 61.5 years (range, 39-78). Nine patients (56%) were White and 3 (19%) were Black. Twelve (75%) patients identified as not Hispanic or Latino. Of the overall population of 31 patients, 7 patients had a disease origin from the uterus, 1 from the ovary, 5 from the retroperitoneum, 3 from the pelvis, and 15 from another.

 of intravenous nab-Sirolimus on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity were observed.

Nab-Sirolimus is the first and only FDA-approved treatment for locally advanced or metastatic malignant unresectable PEComa. The agent was 

approved in this intent-to-treat population

Advanced malignant PEComas are associated with poor prognoses and typically demonstrate local invasion or metastases, according to the presentation from Herzog, University of Cincinnati Cancer Center.1 In the metastatic unresectable setting, the median OS ranges from 16 months with chemotherapy to 29 months with targeted therapy. The presence of nab-Sirolimus on the market represents an important treatment option as the standard of care for patients with this rare cancer.

According to Herzog, more studies are underway investigating nab-Sirolimus to treat malignant PEComa mTOR-driven cancers of gynecologic origin.

Herzog T, Dockery L, Dickson M, et al. Response to treatment with nab-sirolimus in patients with perivascular epithelioid cell sarcoma (PEComa) of gynecologic or peritoneal origin: subgroup analysis from AMPECT. Presented at: Society of Gynecologic Oncology 2024 Annual Meeting on Women's Cancer, March 16-18, 2024. San Diego, CA.

FDA approves sirolimus protein-bound particles for malignant perivascular epithelioid cell tumor. News release. FDA. November 22, 2021. Accessed March 17, 2024. 

Articles

Patients with perivascular epithelioid sarcoma of gynecologic or peritoneal origin experienced durable responses when treated with nab-sirolimus.

Nab-Sirolimus Elicits Responses in Gynecologic/Peritoneal PEComa

Minimal residual disease (MRD) detection by circulating tumor DNA (ctDNA) was prognostic and predictive of disease recurrence and response to adjuvant chemotherapy in patients with stage II/III colorectal cancer (CRC), according to findings from the first interim analysis of the observational BESPOKE study (NCT04264702) presented during the 

“BESPOKE is one of the first and largest studies in the United States looking at a tumor-informed circulating tumor DNA’s ability to inform adjuvant chemotherapy decisions in patients with both stage II and III colorectal cancer,” Pashtoon Murtaza Kasi, MD, MS, medical oncologist and researcher at Weill Cornell Medicine and New York-Presbyterian Hospital, said in his presentation.

Of 295 evaluable patients with stage II (n =130) and stage III (n = 165) CRC, 6.9% (n = 46) of stage II and 22.4% (n = 37) of stage III patients were MRD-positive as identified by ctDNA. There was a significant association between MRD positivity and worse disease-free survival (DFS) outcomes overall (HR, 20.8; 95% CI, 10.0-43.4, 

 <.0001), as well as within each subgroup (stage II: HR, 25.7; 95% CI, 6.8-96.7; stage III: HR, 18.1; 95% CI, 7.3-45.1).

The median DFS was not reached post-surgery among patients who were MRD-negative vs a median DFS of 15.98 months (range, 13.77-20.22) in patients who were MRD-positive.

Among patients who were MRD-positive, those who received adjuvant chemotherapy experienced longer DFS compared with those in the observation group (18.7 vs 6.7; HR, 3.9; 95% CI, 1.3-11.5; 

 =.01). Comparatively, there was no observed benefit to DFS with adjuvant chemotherapy in the MRD-negative group (HR, 1.1; 95% CI, 0.3-3.9; 

“Regardless of the fact if you got [chemotherapy or] didn't get [chemotherapy, there were] very intriguing results: [the] same disease-free survival of nearly 9 months. A benchmark for the pairing of novel therapeutics and clinical trial designs on a large cohort of patients with stage II and III colon cancer,” Kasi explained.

ctDNA clearance at 12 weeks was observed in 39.1% (n = 18) of patients who were MRD-positive, and longer DFS was associated with ctDNA clearance compared with those who remained positive (24.2 months vs 13.8 months; HR, 0.4; 95% CI, 0.1-1.0; 

 =.045). However, these patients still had worse DFS than those who were ctDNA-negative at 4 and 12 weeks (HR, 22.5; 95% CI, 6.8-75.0; 

Disease recurrence was observed in 44.4% (n = 8) of patients who had ctDNA clearance, and all 8 patients were ctDNA-positive before relapse was detected radiologically.

“We also show some very interesting dynamics of ctDNA clearance. The ones who sustain clearance, not surprisingly, are the ones who are all disease-free several years out before the ones who are not transiently clear. Interestingly, 85% of the time, you have molecular recurrence by 15 months. So, as we counsel patients or expect what to see in trials, 15 months is the time point from any kind of molecular recurrence,” Kasi said.

Kasi also highlighted that ctDNA testing provided patients with more feelings of confidence. A reported 73% of patients said that ctDNA results reduced anxiety about cancer recurrence, and 87% felt they were receiving the right treatment after receiving their ctDNA results. Moreover, 92% of patients would continue using ctDNA testing to monitor cancer, and 96% valued the additional information they received from ctDNA results.

Kasi P, Aushev V, Ensor J, et al. Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): Interim analysis of BESPOKE CRC study. 

2024;42(suppl 3):9. doi:10.1200/JCO.2024.42.3_suppl.9

Minimal residual disease detection by ctDNA was predictive and prognostic of disease recurrence and response to adjuvant chemotherapy in patients with CRC.

ctDNA Is Predictive of DFS, Offers Prognostic Tool in CRC

Concurrent adagrasib (Krazati) and pembrolizumab (Keytruda) generated early signals of efficacy in patients with treatment-naïve, advanced non–small cell lung cancer (NSCLC) harboring 

 G12C mutations, particularly in those who had a PD-L1 tumor proportion score (TPS) of at least 50%, according to findings from the phase 2 KRYSTAL-7 trial (NCT04613596) presented at the 

“With longer follow-up, concurrent adagrasib and [pembrolizumab] demonstrated encouraging preliminary activity in patients with PD-L1 greater than 50% and a manageable safety profile,” Marina Garassino, MD, professor of hematology and oncology at the University of Chicago in Illinois and one of the study’s investigators, said of the mid-stage data.

In patients with a PD-L1 TPS of at least 50%, adagrasib and pembrolizumab generated an overall response rate (ORR) of 63% (32/51; 95% CI, 48-76) and a disease control rate (DCR) of 84% (43/51; 95% CI, 12.6-not evaluable [NE]). The ORR seen with the combination compares favorably with the ORR of pembrolizumab, which ranges from 39% to 45% when used as a single agent.

The safety profile of the combination of adagrasib and pembrolizumab was consistent with the known safety profiles of either agent as a monotherapy. Among the 148 patients, treatment-related adverse events (TRAEs) led to permanent adagrasib discontinuation in 6% of patients (n = 9), and 11% (n = 16) of patients discontinued pembrolizumab because of TRAEs. Only 4% (n = 6) of patients discontinued both drugs because of TRAEs. Dose reductions due to TRAEs occurred in 46% (n = 66) of patients, and 59% (n = 88) temporarily discontinued treatment because of TRAEs.

Nausea and diarrhea were the most common TRAEs, occurring at any grade in 51 and 44 patients, respectively. Immune-related TRAEs of any grade occurred in 18% (n = 26) of patients, and immune-related TRAEs grade 3 or higher occurred in 5% (n = 8) of patients. There were 2 grade 5 TRAEs of pneumonitis and pneumonia.

“Sotorasib has already shown a severe hepatotoxicity when combined in the first-line with immune checkpoint inhibitors in treatment of [patients with treatment-naïve NSCLC] and also when it was administered sequentially following a prior immune checkpoint inhibitor, in particular, within 30 days,” Garassino said in her presentation.

However, adagrasib does not share the same hepatotoxicity concerns, potentially because of its steady-state pharmacokinetics (PK) and low peak-to-trough ratio. The administration of adagrasib sequentially or in combination with pembrolizumab is not limited by hepatotoxicity.

In the KRYSTAL-7 trial, treatment-related hepatic events occurred in less than 10% of patients. Alanine transaminase (ALT) and aspartate transaminase (AST) increases were observed in 38 and 32 patients, respectively, but no patient discontinued both adagrasib and pembrolizumab because of an increase in ALT/AST or hepatic TRAEs.

Moreover, hepatic TRAEs, particularly ALT/AST increases, were resolved favorably. The median time to first resolution of increase ALT/AST was 22 days, and resolution occurred in about 80% of cases.

KRYSTAL-7’s phase 2 primary end point is ORR to establish the efficacy of adagrasib monotherapy and in combination with pembrolizumab administered to patients with advanced or metastatic NSCLC. The phase 2 secondary end points are safety, tolerability, duration of response (DoR), progression-free survival (PFS), and PK.

The trial consists of 3 cohorts. Cohort 1a includes patients with a PD-L1 TPS of less than 1% who received adagrasib 400 mg twice daily in combination with pembrolizumab. Cohort 1b had a PD-L1 TPS of less than 1% and received adagrasib monotherapy 600 mg twice daily. Cohort 2 had a PD-L1 TPS of at least 1% and received adagrasib 400 mg twice daily with pembrolizumab.

The median follow-up was 8.7 months for all patients and 10.1 months for patients with PD-L1 TPS of at least 50%. The median time to response was 1.4 months, and the median PFS was not reached (95% CI, 8.2-NE).

Patients were eligible for phase 2 if they had a histologically confirmed diagnosis of unresectable or metastatic NSCLC with a 

“These findings support the initiation of a phase 3 trial evaluating concurrent adagrasib and [pembrolizumab] vs [pembrolizumab] in treatment naïve 

 G12C,” Garassino said in her presentation.

The phase 3 KRYSTAL-7 trial plans to begin enrollment at the end of this year.

 The phase 3 primary end point is PFS, and the secondary end points are safety, tolerability, PK, health-related quality-of-life, overall survival, and DoR.

Garassino MC, Theelan WSME, Jotte R, et al. KRYSTAL-7: Efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at: European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA65.

Mirati presents late-breaking results evaluating the combination of adagrasib and pembrolizumab in first-line non–small cell lung cancer (NSCLC). News release. Mirati. October 17, 2023. Accessed October 20, 2023. 

Phase 2 trial of MRTX849 monotherapy and in combination with pembrolizumab and a phase 3 trial of adagrasib in combination in patients with a KRAS G12C mutation KRYSTAL-7. ClinicalTrials.gov. Updated October 10, 2023. Accessed October 20, 2023.

https://www.clinicaltrials.gov/study/NCT04613596

Concurrent adagrasib and pembrolizumab generated early signals of efficacy in patients with treatment-naïve, advanced non–small cell lung cancer harboring KRAS G12C mutations, particularly in those who had a PD-L1 tumor proportion score of at least 50%.

Sabrina Serani

Articles

Nab-Sirolimus Elicits Responses in Gynecologic/Peritoneal PEComa

ctDNA Is Predictive of DFS, Offers Prognostic Tool in CRC

Pembrolizumab Plus Adagrasib Demonstrates Preliminary Efficacy in KRAS G12C–Mutated NSCLC