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ESMO Targeted Anticancer Therapies Congress

MK-1084 had an acceptable toxicity profile and elicited responses when administered as a monotherapy in patients with 

 G12C–mutated previously treated solid malignancies and in combination with pembrolizumab (Keytruda) in those with treatment-naive non–small cell lung cancer (NSCLC), according to updated data from a phase 1 study presented at the 

2024 ESMO Targeted Anticancer Therapies Congress

In arm 1, 98% of patients who received MK-1084 monotherapy at all doses (n = 55) experienced at least 1 AE; these effects were grade 3 for 35% of patients, grade 4 for 4% of patients, and grade 5 for 5% of patients. A total of 4 patients discontinued study treatment because of toxicity. Moreover, 60% of patients experienced at least 1 AE that was related to treatment; 7% of these AEs were grade 3 and 2% were grade 4. No dose-limiting toxicities (DLTs) were observed.

In arm 2, all patients who received MK-1084 at all doses (n = 31) plus pembrolizumab experienced 1 or more AEs; these effects were grade 3 (32%), grade 4 (10%), and grade 5 (6%). A total of 7 patients in this arm discontinued any study drug because of toxicity. Additionally, 87% of patients experienced 1 or more treatment-related AEs and these effects were grade 3 (39%), grade 4 (3%), and grade 5 (3%). One patient who received MK-1084 at a daily dose of 400 mg plus the immunotherapy experienced DLTs in the form of grade 3 increased aspartate and alanine aminotransferase (AST; ALT).

Efficacy data indicated that in arm 1, single-agent MK-1084 at all doses (n = 55) elicited an objective response rate (ORR) of 29% (95% CI, 18%-43%), with a median time to response of 1.4 months (range, 1.2-6.2). The disease control rate (DCR) was 82% in these patients. When broken down by dose, those who received a daily dose ranging from 25 mg to 200 mg total (n = 33) experienced an ORR of 30% (95% CI, 16%-49%) and a DCR of 79%. In those who received a daily dose of 400 mg or higher total, the ORR was 27% (95% CI, 11%-50%) and the DCR was 86%.

In arm 2, MK-1084 given at all doses plus pembrolizumab (n = 27) led to an ORR of 70% (95% CI, 50%-86%) and a DCR of 85%. The median time to response was again 1.4 months (range, 1.2-4.2). When broken down by dose, those who received the investigative agent at a total daily dose ranging from 25 mg to 200 mg (n = 23) paired with pembrolizumab experienced an ORR and DCR of 70% (95% CI, 47%-87%) and 87%, respectively. In those who received MK-1084 at a total daily dose of 400 mg or higher plus pembrolizumab (n = 4), the ORR was 75% (95% CI, 19%-99%) and the DCR was (75%).

“Antitumor activity for MK-1084 monotherapy was observed in patients with previously treated solid malignancies whose tumors harbored 

 G12C mutations; responses occurred in patients with colorectal cancer [CRC], NSCLC, and other tumor types at 50 mg to 800 mg total daily doses for MK-1084,” Dr Carlos Rojas, of Centro de Investigacion Clinica, Bradford Hill, in Santiago, Chile, said in a presentation of the data. “Antitumor activity for MK-1084 in combination with pembrolizumab was observed in patients with previously untreated NSCLC with a PD-L1 tumor proportion score [TPS] of at least 1% across all doses evaluated.”

 G12C mutations occur frequently in several cancers, they have the highest incidence in those with NSCLC, according to Rojas, who added that inhibition of this target could encourage a proinflammatory tumor microenvironment, which is conducive to success with immunotherapeutic approaches. “ML-1084 is a selective KRAS G12C–GDP inhibitor that has shown promising antitumor activity in preclinical studies,” he said.

The open-label, global, phase 1 study enrolled patients into two arms. Those in arm 1 had locally advanced solid tumors and had previously received at least 1 therapy, and those in arm 2 had treatment-naive metastatic NSCLC with a PD-L1 TPS of 1% or higher. All patients needed to be at least 18 years of age, have confirmed 

 G12C–mutated disease that was also measurable by RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.

Those enrolled in arm 1 received single-agent MK-1084 (n = 55) at the following once-daily dose levels: 25 mg (n = 3), 50 mg (n = 5), 100 mg (n = 8), 200 mg (n = 9), 400 mg (n = 9), or 800 mg (n = 4) with optional twice-daily dose levels of 50 mg (n = 8) and 200 mg (n = 9). Those in arm 2 received MK-1084 at once-daily doses of 25 mg (n = 3), 50 mg (n = 8), 100 mg (n = 5), 200 mg (n = 8), or 400 mg (n = 4), or a twice-daily dose of 50 mg (n = 3), in combination with pembrolizumab given at 200 mg every 3 weeks.

The primary end points of the study were to examine DLTs, adverse effects (AEs), and AEs that led to treatment discontinuation. A key secondary end point was ORR.

The median patient age in arms 1 and 2, respectively, was 64.0 years (range, 36-81) and 68.0 years (49-78); 62% vs 52% of patients were male and more than half of patients in both arms had an ECOG performance status of 1 (65.5% vs 74.2%). In arm 1, 22% of patients had NSCLC, 67% had CRC, 2% had anal cancer, 2% had cervical cancer, 2% had melanoma, 2% had mucinous neoplasm of the appendix, 2% had neuroendocrine cancer, and 2% had pancreatic cancer. In arm 1, 24% had prior 1 line of therapy, 33% received 2 prior lines, 16% received 3 prior lines, and 22% had 4 or more lines; this information was unknown for 5% of patients.

The median follow-up time in arm 1 was 11.1 months (range, 2.1-21.5) and the median exposure duration was 5.7 months (range, 0.2-15.2). At the time of the data cutoff date of November 3, 2023, 38% of patients were still receiving treatment and 62% had discontinued. The most common reason for treatment discontinuation was disease progression (55%) followed by AEs (7%). For arm 2, the median follow-up time was 7.0 months (range, 0.4-17.2) and the median exposure duration was 6.0 months (range, 0.4-15.9). At data cutoff, 84% of patients were still receiving treatment and 16% had discontinued due to disease progression (10%) or AEs (6%).

Additional data showed that within arm 1, those with CRC (n = 37) experienced an ORR of 24% (95% CI, 12%-41%) with a DCR of 78% and a median time to response of 2.6 months (range, 1.2-6.2). Those with NSCLC (n = 12) experienced an ORR of 42% (95% CI, 15%-72%), a DCR of 83%, and a median time to response of 1.4 months (range, 1.2-1.4). Those with other solid tumors (n = 6) experienced an ORR and DCR of 33% (95% CI, 4%-78%) and 100%, respectively; the median time to response in this group was also 1.4 months (range, 1.3-1.5).

In arm 2, those with a PD-L1 TPS ranging from 1% to 49% (n = 13) achieved an ORR of 54% (95% CI, 25%-81%) and a DCR of 77%; the median time to response in this group was 1.4 months (range, 1.2-4.2). In those with a PD-L1 TPS of 50% or higher (n = 14), the ORR and DCR experienced with the doublet was 86% (95% CI, 57%-98%) and 93%, respectively. Again, the median time to response in this group was 1.4 months (range, 1.2-2.6).

Duration of response data were not mature at the time of the analysis, according to Rojas.

In arm 1, the treatment-related AEs (TRAEs) that had an incidence of 10% or higher in either arm included increased AST (grade 1/2, 15%; grade 3/4, 4%), increased ALT (13%; 4%), nausea (16%; 0%), diarrhea (11%; 2%), fatigue (13%; 0%), pruritus (7%; 0%), rash (4%; 0%), and increased alkaline phosphatase (ALP; 4%). In arm 2, the TRAEs that had an incidence of at least 10% in either arm comprised increased ALT (grade 1/2, 26%; grade 3-5, 13%), increased AST (23%; 10%), pruritus (23%; 3%), diarrhea (23%; 0%), rash (10%; 3%), fatigue (13%; 0%), increased ALP (13%; 0%), and nausea (10%; 0%).

“The study has been expanded to additional combinations evaluating MK-1084 in patients with 

 G12C­–mutated cancer,” Rojas concluded.

Rojas CI, Lugowska I, Juergens R, et al. 44O Updated results from a phase I study evaluating the KRAS G12C inhibitor MK-1084 in solid tumors and in combination with pembrolizumab in NSCLC. 

. 2024;9(suppl 102273). doi:10.1016/j.esmoop.2024.102273

MK-1084 had an acceptable toxicity profile when administered as a monotherapy in patients with KRAS G12C–mutated previously treated solid malignancies. 

MK-1084 Alone and Plus Pembrolizumab Shows Early Safety, Activity in KRAS G12C+ Solid Tumors

Treatment with NT219, a first-in-class dual inhibitor of STAT3 and IRS1/2, in combination with cetuximab (Erbitux) displayed a manageable safety profile with anti-tumor activity in patients with HPV-negative recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), according to findings from a phase 1/2 trial (NCT04474470) presented at the 

At the January 25, 2024, data cutoff, interim findings from the study showed that patients treated with the 2 highest dose levels of NT219 (n = 7) achieved an objective response rate (ORR) of 28.6%, with 2 confirmed partial responses (PR). Additionally, there were 3 instances of stable disease for a disease control rate of 71.4%.

“We were encouraged to see anti-tumor activity in HPV-negative patients,” Michael Schickler, PhD, head, Clinical and Regulatory Affairs, Purple Biotech, said in a press release. “There is an unmet medical need for patients in second- and third-line recurrent/metastatic SCCHN, most of them having HPV-negative disease, with relatively short survival of less than nine months. NT219 should continue to be tested to establish better treatment options for this patient population.”

The phase 1/2 study enrolled patients with SCCHN who received up to 2 prior regimens for recurrent/metastatic disease and an ECOG performance status of less than 2. NT219 was given at 5 dose levels: 6 mg/kg; 12 mg/kg; 24 mg/kg; 50 mg/kg; and 100 mg/kg. NT219 was administered in combination with cetuximab until disease progression, unacceptable toxicity, patient withdrawal, or death.

The primary objectives were safety, tolerability, and determination of the recommended phase 2 dose (RP2D) of NT219. Secondary objectives included ORR, duration of response, progression-free survival, overall survival, and pharmacokinetics.

At baseline, the median age in the overall population (n = 17) was 58 years (range, 28-65) and all patients were male. Most patients were White (95%), underwent prior immune checkpoint inhibitor (94%) and platinum-based chemotherapy (82%), had a tumor located in the oral cavity (76%), and negative HPV status (65%). The median number of prior lines of therapy was 2 (range, 1-2); 71% of patients underwent 2 prior lines of therapy.

Additional findings showed that, at a median follow-up of 9.4 months (95% CI, 3.4-10.0), 1 patient who achieved PR at the 50 to 100 mg/kg dose levels was still in response and continuing with treatment; another patient at this dose level was continuing with treatment after experiencing stable disease. At the data cutoff, 8 patients were still alive or had not withdrawn consent.

Study authors highlighted findings from 3 patients. Patient 1 had HPV-negative neck lesions, received frontline cetuximab and radiation and second-line pembrolizumab (Keytruda) plus MCLA-158; this patient experienced a PR per RECIST v1.1 criteria with a 60% decrease in tumor size and withdrew after 6 weeks of treatment with NT219 and cetuximab due to immune-related adverse effects. Patient 2 had HPV-negative neck lesions and received frontline pembrolizumab; this patient experienced a PR of 48% and was still receiving treatment at 40 weeks. Finally, patient 3 had HPV-negative lung lesions, received frontline nivolumab (Opdivo) and second-line pembrolizumab with carboplatin and 5-fluorouracil; this patient experienced stable disease and stayed on treatment for 27 weeks.

In terms of safety, investigators noted that NT219 had a well-tolerated and manageable safety profile up to a dose of 100 mg/kg. The most common any-grade treatment-emergent adverse effects (TEAEs) in the safety population (n = 17) included infusion-related reactions (76.4%), nausea (35.3%), and fatigue (29.4%). Common grade 3 TEAEs consisted of infusion-related reactions (11.8%), hypertension (11.8%), headache (5.9%), and nausea (5.9%). Notably, no grade 4 or 5 TEAEs were observed; the RP2D of NT219 was determined to be 100 mg/kg.

“These positive data support our path forward for NT219 as we plan to initiate a phase 2 study in combination with cetuximab in head and neck cancer in the first half of 2024,” Gil Efron, chief executive officer, Purple Biotech, said in the press release. “We thank the study participants, their families, and clinical researchers for participating in this important study.”

Disclosures: Dr Rosenberg reported consulting/advisory roles for EMD Serono, Astellas, Eisai, Nanobiotix, Novartis, Regeneron, Vaccitech, Galectin, and Privo.

Rosenberg AJ, Kato S, Johnson D, et al. Interim results of a phase 1/2 trial of NT219 in combination with cetuximab in patients with recurrent/metastatic (r/m) squamous cell carcinoma of the head and neck (SCCHN). 

. 2024;9(suppl 1):1-7. doi:10.1016/esmoop/esmoop102270

Purple Biotech presents data of its phase 1 head & neck cancer of NT219 in combination with cetuximab at ESMO TAT Congress 2024. News release. Purple Biotech Ltd. February 27, 2024. Accessed March 18, 2024. https://finance.yahoo.com/news/purple-biotech-presents-data-phase-120000569.html

NT219 in combination with cetuximab was safe and effective in patients with recurrent/metastatic squamous cell carcinoma of the head and neck. 

NT219 Plus Cetuximab Demonstrates Efficacy, Tolerability in SCCHN

Treatment with TNO155 in combination with spartalizumab (PDR001) or ribociclib (Kisqali) led to disease control and was well tolerated in heavily pretreated patients with advanced solid tumors, according to data from the phase 1b CTNO155B12101 trial (NCT04000529) presented at the 2024 ESMO Targeted Anticancer Therapies Congress.

Findings showed that patients treated with TNO155 plus spartalizumab across all doses (n = 57) experienced a disease control rate (DCR) of 26.3%, including a partial response (PR) rate of 1.8%, a stable disease (SD) rate of 24.6%, and a progressive disease (PD) rate of 50.9%. Response was unknown in 22.8% of patients. Notably, the recommended dose of 60 mg of TNO155 once per day for 2 weeks on and 1 week off, plus 300 mg of spartalizumab once every 3 weeks (n = 19), elicited a DCR of 31.6% with PR and SD rates of 5.3% and 26.3%, respectively. Response was unknown in 21.1% of patients in this subset.

Additionally, TNO155 plus ribociclib did not generate any responses across all dose levels (n = 46); however, the combination demonstrated a DCR of 13.0%. The PD rate was 67.4%, and response was unknown for 19.6% of patients.

Notably, patients treated with the recommended dose of TNO155 at 40 mg plus 200 mg of ribociclib once per day on a 2-weeks-on, 1-week-off schedule (n = 9) experienced a DCR of 44.4% and a PD rate of 55.6%.

Regarding safety, no fatal treatment-related adverse effects (TRAEs) occurred in patients treated with either combination. Three fatal AEs were reported in the TNO155/spartalizumab cohort, including ischemic stroke (n = 1), esophageal perforation and sepsis (n = 1), and pneumonia (n = 1); however, no fatal AEs occurred in patients treated at the recommended dose of TNO155/spartalizumab.

For all patients treated with TNO155/spartalizumab, the rates of any-grade AEs leading to dose reduction and treatment discontinuation were 14.0% and 8.8%, respectively. For those treated at the recommended dose, those rates were both 15.8%. In the overall TNO155/ribociclib cohort, the rates of any-grade AEs leading to dose reduction and treatment discontinuation were 15.2% and 10.9%, respectively. At the recommended dose of TNO155/ribociclib, any-grade AEs led to dose reductions in 22.2% of patients, and no patients discontinued treatment due to AEs.

“The safety profiles of the combinations were consistent with those observed with each single agent, and no new safety signals were identified,” lead study author Omar Saavedra, MD, of the Early Drug Development Unit (phase 1 Unit) at Vall d'Hebron Institute of Oncology in Barcelona, Spain, said in a presentation of the data.

TNO155 is a selective, orally bioavailable allosteric SHP2 phosphatase inhibitor intended to block tumor-promoting and immune-suppressive RTK signaling in 

-driven tumors. Based on preclinical studies that demonstrated antitumor activity for TNO155 in combination with a murine anti–PD-1 antibody, as well as with ribociclib, the phase 1 trial was designed to assess the safety and tolerability of the 2 combinations in patients with advanced solid tumors.

CTNO155B12101 was a dose-escalation study that enrolled patients at least 18 years of age who had advanced solid tumors with evaluable disease per RECIST v1.1 criteria. An ECOG performance status of 0 or 1 was also required.

Enrolled patients with advanced head and neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC), colorectal cancer (CRC), or 

 wild-type non–small cell lung cancer (NSCLC) were assigned to receive TNO155 in combination spartalizumab. The PD-1 inhibitor was given at 300 mg once every 3 weeks across all cohorts, and TNO155 was administered on a 2-weeks-on, 1-week-off schedule at doses of 5 mg twice per day (n = 6), 10 mg twice per day (n = 5), 20 mg once per day (n = 5), 20 mg twice per day (n = 5), 30 mg twice per day (n = 6), 40 mg twice per day (n = 7), 50 mg twice per day (n = 3), 60 mg once per day (n = 19), and 60 mg twice per day (n = 1).

The TNO155/ribociclib cohort included patients with any advanced solid tumor. Treatment regimens consisted of TNO155 at 20 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day (n = 3); TNO155 at 20 mg twice per day plus ribociclib at 150 mg once per day for 3 weeks on and 1 week off (n = 5); TNO155 at 30 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off (n = 9); TNO155 at 40 mg once per day plus ribociclib at 200 mg once per day for 2 weeks on and 1 week off (n = 9); TNO155 at 40 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day (n = 5); TNO155 at 40 mg once per day plus ribociclib at 150 mg once per day for 3 weeks on and 1 week off (n = 4); TNO155 at 40 mg once per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off (n = 5); TNO155 at 40 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off (n = 1); and TNO155 at 60 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day (n = 5).

The primary end points included safety and tolerability, as well as establishing the maximum tolerated dose and/or recommended dose. Secondary end points consisted of pharmacokinetics and preliminary antitumor activity. Changes in 

 mRNA expression in tumors was a key exploratory end point.

Among patients treated across all doses of TNO155/spartalizumab, the median age was 57.0 years (range, 30-77), and most patients were male (61.4%) and White (71.9%). Histology included CRC (59.6%), ESCC (3.5%), HNSCC (14.0%), NSCLC (21.1%), and other (1.8%). The median number of prior antineoplastic regimens was 3.0 (range, 1-9). Additionally, the rates of patients with an ECOG performance status of 0 and 1 were both 49.1%, and performance status data were missing for 1 patient (1.8%).

In all patients treated with TNO155/ribociclib, the median age was 57.5 years (range, 29-81), and half of patients were male. The majority of patients were White (67.4%) and had an ECOG performance status of 0 (69.6%). Cancer diagnosis included CRC (58.7%), ESCC (6.5%), HNSCC (2.2%), NSCLC (15.2%), and other (17.4%). Patients in this group received a median of 4.0 (range, 1-9) prior antineoplastic regimens.

As of the November 1, 2023, data cutoff, all patients enrolled in the TNO155/spartalizumab cohort had discontinued treatment. Reasons for discontinuation included PD (77.2%), AEs (8.8%), death (7.0%), patient decision (5.3%), and physician decision (1.8%). In the TNO155/ribociclib cohort, 45 of 46 patients (97.8%) had discontinued treatment due to PD (80.4%), AEs (10.9%), death (2.2%), and patient decision (4.3%).

Additional safety data for the TNO155/spartalizumab combination showed that all patients experienced any-grade AEs, and 68.4% encountered grade 3 or higher AEs. The rates of any-grade and grade 3 or higher TRAEs were 94.7% and 26.3%, respectively.

The most common AEs with TNO155/spartalizumab included increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased creatine phosphokinase (CPK), anemia, thrombocytopenia, increased N-terminal prohormone of brain natriuretic peptide, peripheral edema, and diarrhea.

Furthermore, dose-limiting toxicities (DLTs) reported across various dose levels for TNO155/spartalizumab included grade 3 decreased ejection fraction (n = 1; dose level, TNO155 at 20 mg once per day for 2 weeks on and 1 week off), grade 2 decreased ejection fraction (n = 1; dose level, TNO155 at 20 mg once per day for 2 weeks on and 1 week off), grade 3 autoimmune encephalopathy (n = 1; dose level, TNO155 at 60 mg once per day for 2 weeks on and 1 week off), grade 3 febrile neutropenia (n = 1; dose level, TNO155 at 20 mg twice per day for 2 weeks on and 1 week off), grade 3 rhabdomyolysis (n = 1; dose level, TNO155 at 40 mg twice per day for 2 weeks on and 1 week off), grade 3 localized edema (n = 1; dose level, TNO155 at 50 mg twice per day for 2 weeks on and 1 week off), and grade 2 swelling (n = 1; dose level, TNO155 at 50 mg twice per day for 2 weeks on and 1 week off).

Additional safety data for TNO155/ribociclib showed that the most common any-grade AEs consisted of thrombocytopenia, increased AST, increased CPK, anemia, increased ALT, diarrhea, neutropenia, pyrexia, and peripheral edema.

DLTs reported in patients treated with TNO155/ribociclib included grade 3 dyspnea and grade 3 pneumonitis (n = 1; dose level, TNO155 at 40 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day); grade 3 pulmonary edema (n = 1; dose level, TNO155 at 60 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day); grade 3 diarrhea and grade 3 decreased platelet count (n = 1; dose level, TNO155 at 60 mg once per day for 2 weeks on and 1 week off plus continuous ribociclib at 200 mg once per day); grade 2 decreased ejection fraction (n = 1; dose level, TNO155 at 40 mg once per day plus ribociclib at 150 mg once per day for 3 weeks on and 1 week off); grade 4 thrombocytopenia (n = 1; dose level, TNO155 at 30 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off); grade 3 decreased neutrophil count (n = 1; dose level, TNO155 at 30 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off); grade 3 urate increase and grade 1 increased blood creatinine (n = 1; dose level, TNO155 at 30 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off); grade 3 pneumonitis and grade 4 decreased platelet count (n = 1; dose level, TNO155 at 40 mg twice per day plus ribociclib at 200 mg once per day for 3 weeks on and 1 week off); and grade 3 hypertransaminasemia (n = 1; dose level, TNO155 at 40 mg once per day plus ribociclib at 200 mg once per day for 2 weeks on and 1 week off).

Pharmacokinetic data for both combinations demonstrated that drug exposures were consistent for each agent compared with their single-agent use from past studies. Furthermore, more than 50% of patients who received TNO155 at doses of at least 40 mg once per day experienced suppression of 

 mRNA, which is a marker of SHP2 inhibition.

Saavedra O, Machiels JP, Soo R, et al. A dose-escalation study of TNO155 (TN) in combination with spartalizumab (SPA) or ribociclib (RIB) in adults with advanced solid tumors. 

. 2024;9(suppl 1):1-11. doi:10.1016/esmoop/esmoop102271

TNO155 plus spartalizumab or ribociclib was well tolerated and demonstrated disease control in patients with advanced solid tumors.

TNO155 Plus Spartalizumab or Ribociclib Elicits Disease Control, Is Safe in Advanced Solid Tumors

Treatment with the antibody-cytokine fusion protein L19-IL12 led to stable disease (n = 10) and partial response (PR; n = 1) lasting 4 months in patients with metastatic solid tumors (n = 22), according to findings from the phase 1 dose-escalation DODEKA trial (NCT04471987) that were presented at the 

“L19-IL12 is well tolerated between 0.1 and 8 μg/kg,” Giuseppe Curigliano, MD, PhD, lead study author, full professor of Medical Oncology at the University of Milano, and chief of the Clinical Division of Early Drug Development at European Institute of Oncology, in Milano, Italy, said in a presentation of the data.

IL-12 is a potent immunostimulatory cytokine that strengthens T- and natural killer cell–mediated antitumor immunity. The agent is designed to deliver IL-12 to the tumor microenvironment through conjugation to the tumor-targeting antibody L19, which binds to the alternatively spliced extra domain B of fibronectin—an element of the stroma found in most solid tumors and undetectable in most healthy tissues. In prior mouse models, L19-IL12 was shown to increase the therapeutic index, leading to strong antitumor activity.

To be eligible for inclusion in the first-in-human study, patients had to be between the ages of 18 and 80 years, have an ECOG performance status of 2 or less, and a life expectancy of at least 12 weeks. Histological or cytological diagnosis of advanced or metastatic solid carcinoma for which checkpoint inhibition is approved was also required. Only patients who had experienced clinical benefit (≥3-month progression-free survival) from prior treatment with a checkpoint inhibitor–based regimen were included in the study cohort.1

Patients with other treatment options that had curative or life-prolonging potential were excluded from enrollment. Other exclusion criteria included autoimmune disease; inadequate liver, kidney, and heart function; inadequate hematologic values; acute vascular events within 6 months; pregnancy or breast feeding, surgery; participation in a clinical trial or exposure to anticancer therapy within 4 weeks prior to the start of study therapy; and any severe concomitant condition which makes it undesirable for the patient to participate.

During dose escalation, patients will be sequentially assigned to 8 dose levels (0.1 μg/kg to 16 μg/kg) until the dose-limiting toxicity (DLT) rate reaches 33% in a cohort of 2 to 6 patients. Once the recommended dose is established, another 40 patients will receive IL12-L19L19 in dose expansion, including 10 patients with melanoma, 10 with non–small cell lung cancer (NSCLC), and 20 with other solid tumors. Curigliano noted that the latter cohort will be amended to include 10 patients with a particular tumor type in the event that promising signs of activity are seen in the dose-escalation phase.1,2

According to the protocol, patients will receive 8 weekly intravenous infusions of IL12-L19L19, followed by biweekly administration as maintenance until disease progression, unacceptable toxicity, consent withdrawal, or investigator decision.

Regarding baseline demographics, the median patient age was 62 years (range, 37-76), with 8 reported female patients and 12 reported male patients. Melanoma and NSCLC represented the most common tumor types (n = 6 and n = 5, respectively).1

Additional findings from the study showed that treatment-related adverse effects (TRAEs) that occurred in at least 1 patient in order of frequency were pyrexia, chills, fatigue, decreased lymphocyte count, increased aspartate (AST) aminotransferase, cytokine release syndrome, increased alanine (ALT) aminotransferase, headache, decreased white blood cell count, anemia, arthralgia, asthenia, increased gamma-glutamyl transferase, nausea, increased amylase, decreased appetite, leukopenia, increased lipase, lymphopenia, myalgia, and decreased platelet count.

A total of 22 patients treated in cohorts 1 through 8 were evaluable for DLTs. One DLT occurred in cohort 3 (0.5 μg/kg) of grade 3 AST and ALT elevation. Two DLTs occurred in cohort 8 (16 μg/kg) of grade 3 syncope and patient withdrawal owing to TRAEs.

Serum pharmacokinetics of L19-IL12 were also evaluated at the 0.5-, 1-, 2-, 4-, and 8-μg/kg dose levels. “L19-IL12 shows a short and dose proportional circulatory half-life, but nuclear medicine studies with radiolabeled L19 antibody showed prolonged residence time in the tumor,” Curigliano reported.

Pharmacodynamics were also evaluated in the context of serum biomarkers of IL-12 activity. Results showed a substantial increase in serum concentration of IFN-γ (pg/mL), IP-10 (ng/mL), Neopterin (nmol/L) and IL6 (pg/mL) 24 hours following administration of L19-IL12 across the 0.5, 1, 2, 4, 8, and 16 μg/kg dose levels.

Curigliano concluded by sharing a case study illustrating preliminary signs of activity with the agent. The patient was a 68-year-old female who had received a diagnosis of triple-negative breast cancer in 2017. The patient had experienced progressive disease within months of receiving both carboplatin plus paclitaxel and doxorubicin plus paclitaxel before undergoing mastectomy with lymphadenectomy resulting in complete remission. Despite subsequent therapy with PDR-001, LAG-525, and canakinumab (Ilaris) the patient again developed progressive disease. Upon enrollment in cohort 5 (2.0 μg/kg) of the study at the Istituto Europeo di Oncologia, in Milan, the patient achieved partial response on CT imaging with IL12-L19L19.

Editor’s Note: Dr Curigliano reported being a board member for Ellipses; consultant for Lilly, Novartis, Seagen, Pfizer, Roche, Menarini, Gilead, and Exact Sciences; his institute receiving research grants from MSD and AstraZeneca; and serving on the speakers bureau for Lilly, Novartis, Seagen, Pfizer, Roche, Menarini, Gilead, and Exact Sciences.

Curigliano G, Belli C, Colombo I, et al. Phase I dose-escalation trial with tumor-targeted interleukin-12 (IL12-L19L19) in patients with solid tumors. Presented at: 2024 ESMO Targeted Anticancer Therapies Congress. February 26-28, 2024; Paris, France. Abstract 26O.

Mach N, Belli C, Fernandez E, et al. Phase I dose-escalation trial with tumor-targeted interleukin-12 (IL12-L19L19) in patients with solid tumors. 

. 2023;34(suppl 2):S629-S630. doi:10.1016/j.annonc.2023.09.2176

A high proportion of patients with metastatic solid tumors experienced stable disease following treatment with the immunocytokine in the DODEKA trial. 

Targeted Delivery of IL-12 Shows Preliminary Antitumor Activity in Advanced Solid Tumors 

Treatment with the selective FGFR2/3 inhibitor ABSK061 was well tolerated and elicited responses among patients with advanced solid tumors harboring 

 alterations, according to data from a first-in-human phase 1 trial (NCT05244551) presented at the 2024 ESMO Targeted Anticancer Therapies Congress.

Findings showed that patients evaluable for efficacy (n = 8) experienced an overall response rate (ORR) of 37.5%, which was comprised entirely of partial responses (PRs). The disease control rate (DCR) was 75%. Among 3 of the patients to achieve a PR, 1 patient had non–small cell lung cancer (NSCLC) and received 4 prior lines of therapy; another patient presented with urothelial carcinoma and had received 2 prior lines of therapy; and the third patient had gastric cancer with 2 prior lines of therapy.

In the safety population (n = 29), no dose-limiting toxicities (DLTs) were reported during dose escalation. Treatment-related adverse effects (TRAEs) were generally low grade and reversible, and no patients discontinued treatment due to TRAEs. The most common any-grade TRAEs were increased aspartate aminotransferase (AST) and increased alanine aminotransferase (ALT), which each occurred in 31% of patients.

Regarding AST/ALT elevation, lead study author Ji Zhu, MD, noted that nearly half of patients in the safety population had liver metastases.

“Dose-escalation data validate ABSK061 as the first highly selective FGFR2/3 inhibitor that targets driver alterations,” Zhu said in a presentation of the data. Zhu is a member of the Department of Radiotherapy Oncology at Zhejiang Cancer Hospital in Hangzhou, China.

Preclinical models demonstrated that ABSK061 exhibited higher selectivity for FGFR2/3 compared with FGFR1, informing the hypothesis that this selectivity could lead to decreased toxicities and improved efficacy in clinical trials.

The open-label, phase 1 study enrolled patients with solid tumors who progressed on, were intolerant to, or declined standard-of-care therapy.1,2 Patients were required to have an ECOG performance status of 0 or 1; a life expectancy of at least 3 months; and adequate organ and bone marrow function.

During dose escalation, patients received ABSK061 at 5 mg twice per day (n = 1), 10 mg twice per day (n = 1), 20 mg twice per day (n = 1), 35 mg twice per day (n = 3), 50 mg twice per day (n = 3), 75 mg twice per day (n = 7), 100 mg twice per day (n = 3), or 150 mg once per day (n = 4). Two cohorts also examined recommended doses for expansion (RDEs) at 150 mg once per day (n = 3) and 75 mg twice per day (n = 3). Enrollment is ongoing in the RDE cohorts, where patients are required to have activating 

Incidence of DLTs and AEs served as the primary end points of the study. Secondary end points included ORR, duration of response, DCR, progression-free survival, and pharmacokinetics.2

In the safety population, the median age was 54.0 years (range, 46.0-63.0), and 44.8% of patients were female. The majority of patients were Asian (96.6%) and had an ECOG performance status of 1 (93.1%). Prior lines of systemic therapy included 0 (3.4%), 1 (24.1%), 2 (37.9%), and 3 or more (34.5%). Notably, 93.1% of patients received prior chemotherapy, and 58.6% were previously treated with immunotherapy.1

Tumor types included bladder cancer (3.4%), cervical cancer (13.8%), cholangiocarcinoma (10.3%), colorectal cancer (10.3%), esophageal cancer (3.4%), gastric cancer (17.2%), gastroesophageal cancer (3.4%), NSCLC (10.3%), pancreatic cancer (6.9%), sarcoma (10.3%), small cell lung cancer (3.4%), and other (6.9%).

Additional safety data showed that other common any-grade TRAEs reported in at least 15% of the safety population included retinal pigment epithelial dystrophy/central serous retinopathy (RPED/CSR; 20.7%), increased alkaline phosphatase (17.2%), anemia (17.2%), hyperphosphatemia (17.2%), and diarrhea (17.2%). Grade 3 or higher increased AST and increased ALT each occurred in 3.4% of patients. Notably, all instances of RPED/CSR and hyperphosphatemia were grade 1 and reversible.

The rates of stomatitis, dry mouth, nail toxicity, alopecia, and palmar-plantar erythrodysesthesia were 10.3%, 6.9%, 3.4%, 3.4%, and 3.4%, respectively. No treatment-related dry eye was reported.

Zhu J, Song Z, Zhao Y, et al. First-in-human study of ABSK061: A selective fibroblast growth factor receptor (FGFR) 2/3 inhibitor for treating patients with advanced solid tumors. 

A study to assess safety, tolerability, and pharmacokinetics of ABSK061 in patients with advanced solid tumors. ClinicalTrials.gov. Updated November 16, 2023. Accessed March 6, 2024. 

https://clinicaltrials.gov/study/NCT05244551

ABSK061 was well tolerated and elicited responses in patients with advanced solid tumors harboring FGFR2/3 alterations.

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