ESMO 2024: Showcasing Advancement in ADC Development Pipline with New Data in Tumor Types with High Unmet Needs

During the upcoming European Society for Medical Oncology (ESMO) Congress being held in Barcelona, September 13-17, 2024, expect presentations to include new data on mirvetuximab soravtansine (IMGN853; Elahere®; AbbVie) and the investigational c-Met targeting Antibody-drug Conjugates, telisotuzumab vedotin (AbbV-399; Teliso-V) and telisotuzumab adizutecan (ABBV-400).

Antibody-drug Conjugates (ADCs) being developed by AbbVie’s dedicated team of researchers and scientists are designed to target protein biomarkers such as folate receptor-alpha (FRα) and c-Met (MET protein) which are over-expressed across various tumor types and are associated with poor prognoses. Using these biomarkers as targets, these ADCs deliver potent ‘payloads’ specifically to the tumor.[1][2][3][4][5][6][7][8][9]

Mirvetuximab soravtansine
Mirvetuximab soravtansine is a first-in-class ADC that includes a folate receptor-alpha binding antibody, a cleavable linker, and the maytansinoid payload DM4, a potent tubulin inhibitor designed to kill the targeted cancer cells.

The drug was approved on November 14, 2022, and is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Patients were selected for therapy based on an FDA-approved VENTANA FOLR1 (FOLR-2.1) RxDx Assay, an approved companion diagnostic designed to select patients for the approved indication.

A leading cancer
Ovarian cancer is the leading cause of death from gynecological cancers in the United States. Each year, approximately 20,000 patients are diagnosed. Most patients present with late-stage disease and will typically undergo surgery followed by platinum-based chemotherapy. Unfortunately, the majority of patients will experience a recurrence of their disease and require multiple subsequent lines of therapy, with decreasing efficacy and tolerability. Patients who initially respond to platinum-based chemotherapy and relapse 6 months or longer after the initial treatment were classified as platinum-sensitive, while patients who relapse within under 6 months after platinum-based chemotherapy were considered platinum-resistant.

Platinum-based chemotherapy remains the most active treatment for earlier lines of ovarian cancer. The benefit of retreatment with platinum is generally less with each subsequent line of therapy. While platinum-based doublets predominate treatment for front- and second-line patients based on results from randomized trials, there is no generally accepted standard of care with a clear efficacy benchmark based on prospective trials in third-line or later patients, particularly those whose cancers have progressed on PARP inhibitors.

Although the safety and efficacy of mirvetuximab soravtansine have not been established for platinum-sensitive ovarian cancer, the drug may be the first treatment option to offer an alternative to patients who have not responded to or are no longer responding to treatment with platinum-based chemotherapy

Soraya
Approval of mirvetuximab soravtansine was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. This study with a total of 104 participating patients with measurable disease who received mirvetuximab soravtansine, demonstrated an overall response rate (ORR) of 31.7% (95% CI: 22.9, 41.6) with a median duration of response of 6.9 months (95% CI: 5.6, 9.7). The approval of mirvetuximab soravtansine is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer.

PICCOLO trial
During the ESMO meeting, data from the primary analysis of the single-arm Phase 2 PICCOLO trial IMGN853-0419 (NCT05041257) evaluating the efficacy and safety of investigational mirvetuximab soravtansine monotherapy in heavily pre-treated patients with FRα positive, platinum-sensitive ovarian cancer (PSOC). The primary endpoint is the objective response rate (ORR), and the key secondary endpoint is the duration of response (DOR).

The PICCOLO study was designed to statistically rule out an objective response rate of 28% or lower, as excluded by the lower bound of the confidence interval, a response rate that has been observed with non-platinum, single-agent chemotherapy in platinum-sensitive disease. Patients with PSOC with multiple prior lines of platinum-based therapy or who are ineligible for platinum-based therapy, as in the population in PICCOLO, have no established benchmark standard of care, particularly after disease progression on a PARP inhibitor.

The PICCOLO trial results showed that the study met its primary endpoint with an objective response rate (ORR) of 51.9% (95% CI 40.4, 63.3), including 6 complete and 35 partial responses.

Among the 79 enrolled patients participating in this study, 81% had prior poly (ADP-ribose) polymerase inhibitors (PARPi) treatment; 74.7% of whom progressed while on PARPi. The median duration of response (DOR), a key secondary endpoint, was 8.3 months (95% CI 5.5, 10.8), and median progression-free survival (PFS), an additional secondary endpoint, was 6.9 months (95% CI 5.9, 9.6). The safety profile of mirvetuximab soravtansine was consistent with findings from previous studies, and no new safety concerns were identified. The most common treatment-emergent adverse events (TEAEs) (grade ≥ 3) were blurred vision (10%), dry eye (3%), nausea (1%), keratopathy (4%), and diarrhea (3%).

AbbVie previously announced positive topline results from the study in June 2024. with additional data to be presented at the 2024 ESMO conference.

“There is an urgent patient-driven unmet need to identify novel, effective and tolerable therapies for patients with platinum-sensitive ovarian cancer, including the PARPi pre-treated setting where diminished response to subsequent platinum-based chemotherapy has been reported,” noted Angeles Alvarez Secord, M.D., M.H.Sc., from the Duke Cancer Institute.

“The response rate seen with mirvetuximab soravtansine in PICCOLO highlights the potential of mirvetuximab soravtansine for platinum-sensitive ovarian cancer patients.”

Mirvetuximab soravtansine is also being studied in platinum-sensitive ovarian (PSOC) in the Phase 3 GLORIOSA trial (NCT05445778), in combination with bevacizumab (Avastin®; Genentech/Roche) versus bevacizumab alone, in maintenance after second-line platinum-doublet therapy.

Additionally, the multicenter, open-label, Phase 2 study IMGN853-0420 (NCT05456685), is investigating the combination of mirvetuximab soravtansine with carboplatin (Paraplatin®) as second-line treatment of PSOC with a wider range of FRα expression.

Telisotuzumab vedotin (ABBV 399; Teliso-V)
Patient-reported outcome (PRO) data from the ongoing Phase 2 LUMINOSITY trial (M14-239) (NCT03539536) of telisotuzumab vedotin, in c-Met protein over-expressing, epidermal growth factor receptor (EGFR) wild-type, advanced/metastatic non-squamous non-small cell lung cancer (NSCLC) patients, will be presented at the ESMO meeting.

The endpoints of the LUMINOSITY trial include overall response rate (ORR), duration of response (DoR), disease control rate (DCR), and progression-free survival (PFS) per independent central review (ICR) as well as overall survival (OS). AbbVie previously announced positive topline results from the LUMINOSITY study in November 2023.

Trends in PROs observed in LUMINOSITY will be further evaluated in the ongoing Phase 3 TeliMET NSCLC-01 trial (NCT04928846) in which participating patients will be treated with telisotuzumab vedotin or docetaxel (Taxotere®; Sanofi) at a 1:1 ratio.

“The data at ESMO showcase the depth of our ADC pipeline and highlights the significant progress we are making across key programs in various stages of development, as we strive to deliver new and innovative medicines for patients in need,” explained Daejin Abidoye, M.D., vice president, head of solid tumors, oncology development, AbbVie.

“A testament to these efforts is our plan to submit telisotuzumab vedotin for accelerated approval as a monotherapy in patients with previously treated c-Met overexpressing, epidermal growth factor receptor (EGFR) wild-type non-squamous non-small cell lung cancer in Q3 2024.”

The accelerated approval submission for telisotuzumab vedotin will be reviewed under the US Food and Drug Administration’s (FDA) real-time oncology review program with an approval decision anticipated in 2025.

AbbVie announced FDA breakthrough therapy designation for telisotuzumab vedotin in 2022.

Telisotuzumab adizutecan (ABBV-400)
New safety and efficacy data from a Phase 1 study (NCT05029882) of telisotuzumab adizutecan (ABBV-400), a next-generation, potential best-in-class c-Met directed ADC, highlights the potential of telisotuzumab adizutecan in previously-treated NSCLC and gastroesophageal cancer (GEA) patients, and are supportive of further exploration of this novel ADC in these tumor types and other solid tumors. The study was designed to explore the recommended Phase 2 dose (RP2D) and dose escalation.

Preliminary data show that among 48 previously treated EGFR wild-type non-squamous NSCLC patients, antitumor activity was observed with telisotuzumab adizutecan when dosed at 2.4 and 3.0 mg/kg administered once every 3 weeks (n=39 and 9, respectively), with a confirmed ORR of 43.8% and clinical benefit rate of 85.4%. The most common (≥10%) TEAEs (grade ≥ 3) were anemia (25%) and neutropenia (15%). Additional endpoints (such as progression-free survival), the association between c-Met protein expression and treatment response, and detailed safety data will be presented at the meeting.

In gastroesophageal cancer patients, the preliminary data show that among 42 patients, antitumor activity was observed at a dose of telisotuzumab adizutecan of 3.0 mg/kg administered once every 3 weeks, with a confirmed ORR of 28.6%. The clinical benefit rate was 71.4%. The most common (≥20%) TEAEs (any grade) were gastrointestinal (76.2%), anemia (66.7%), nausea (47.6%), thrombocytopenia and constipation (26.2% each), and neutropenia (23.8%). Additional safety and efficacy data will be presented at the meeting.

Telisotuzumab adizutecan (ABBV-400) is also being evaluated in a Phase 1b basket study (NCT06084481) in advanced solid tumors as a monotherapy and a Phase 2 study (NCT06107413) in second-line metastatic colorectal cancer (CRC) in combination with fluorouracil, folinic acid, and bevacizumab.

Same parental antibody
Telisotuzumab vedotin (ABBV-399; Teliso-V) and telisotuzumab adizutecan (ABBV-400) both target c-Met with the same parental antibody but have different designs and mechanisms of action.10,11 Teliso-V, AbbVie’s most advanced c-Met targeted ADC in development, utilizes monomethyl auristatin E (MMAE), a potent microtubule polymerization inhibitor payload.[10]

Telisotuzumab adizutecan or ABBV-400, a next-generation c-Met targeted ADC utilizes a novel, proprietary topoisomerase 1 inhibitor (Top1i) payload. [11]

ABBV-706
The same payload is also used in another ADC, ABBV-706, an investigational drug targeting seizure-related 6 homolog (SEZ6), a transmembrane protein that is over-expressed in many tumor types with high unmet need, including small cell lung cancer (SCLC), neuroendocrine carcinomas (NECs), and central nervous system (CNS) tumors.[12]

ABBV-706 is investigated in an open-label, phase 1, first-in-human, dose-escalation, and expansion study (NCT05599984) which evaluated the preliminary safety, tolerability, pharmacokinetics (PK), and antitumor activity of ABBV-706 as monotherapy and in combination with budigalimab (ABBV 181; an investigational PD-1 inhibitor), carboplatin, or cisplatin, and determine the recommended phase 2 dose (RP2D) of ABBV-706. [12][13]

The dose escalation part of the study, which enrolled enrolled adult 49 patients (≥18 years) with relapsed/refractory SCLC (n=22 [45%]), 5 patients with high-grade CNS tumors n=5 [10%], and 22 patients with high-grade NEN (n=22 [45%]), following the Bayesian optimal interval design, was administered IV at 1.3–3.5 mg/kg doses Q3W in 21-d cycles.

The median age was 64 yr (range 32–81) and the median prior lines of therapy were 2.5 (range 1–6). The study results showed that 2 patients had dose-limiting toxicity (1 Grade 4 leukopenia and neutropenia lasting >7 d at 3.0 mg/kg and 1 Grade 4 thrombocytopenia at 3.5 mg/kg). TEAEs occurred in 45 (92%) patients with the most frequent being anemia (51%), fatigue (41%), neutropenia (31%), and leukopenia (31%). Grade ≥3 TEAEs occurred in 28 (57%) patients and were mainly hematologic, including neutropenia (29%), anemia (27%), and leukopenia (25%). Gastrointestinal TEAEs (all G1/2) were seen in 55% of patients, with the most common being nausea (27%) and vomiting (18%). The results further demonstrated a maximum tolerated dose (MTD) of 3 mg/kg IV Q3W.[13]

The investigational drug showed an approximate dose-proportional increase in exposure with an elimination half-life of approximately 7 days across doses. The confirmed overall objective response rate (ORR) was 21% (7 partial responses [PR]); 40% (6/15) for SCLC and 6% (1/18) for NEN.[13]

The results of this study were presented at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO). [13]

More studies
During the upcoming ESMO meeting, AbbVie will also present real-world data on the prevalence, stability, and prognostic value of c-Met protein overexpression in NSCLC from the METPRO and METEXPRESS studies at the meeting.

Clinical trials
A Study of Mirvetuximab Soravtansine in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (SORAYA) – ClinicalTrials.gov ID NCT04296890
Mirvetuximab Soravtansine Monotherapy in Platinum-Sensitive Epithelial, Peritoneal, and Fallopian Tube Cancers (PICCOLO) – ClinicalTrials.gov ID NCT05041257
Mirvetuximab Soravtansine With Bevacizumab Versus Bevacizumab as Maintenance in Platinum-sensitive Ovarian, Fallopian Tube, or Peritoneal Cancer (GLORIOSA) – ClinicalTrials.gov ID NCT05445778
Mirvetuximab Soravtansine (MIRV) With Carboplatin in Second-line Treatment of Folate Receptor Alpha (FRα) Expressing, Platinum-sensitive Epithelial Ovarian Cancer – ClinicalTrials.gov ID NCT05456685
Study of Telisotuzumab Vedotin (ABBV-399) in Participants With Previously Treated c-Met+ Non-Small Cell Lung Cancer – ClinicalTrials.gov ID NCT03539536
Study to Assess Adverse Events and Change in Disease Activity in Adult Participants With Select Advanced Solid Tumor Indications Receiving Intravenous (IV) ABBV-400 – ClinicalTrials.gov ID NCT06084481
Study to Assess Adverse Events and Change in Disease Activity in Adult Participants With Advanced Solid Tumors Receiving Intravenous (IV) ABBV-400 as Monotherapy and in Combination With IV Bevacizumab – ClinicalTrials.gov ID NCT05029882
Study to Evaluate Adverse Events, Change in Disease Activity, and How ABBV-706 Moves Through the Body When Intravenously (IV) Infused Alone or in Combination With IV Infused Budigalimab, Cisplatin, or Carboplatin in Adult Participants With Advanced Solid Tumors – ClinicalTrials.gov ID NCT05599984

Highlights of prescribing information
Mirvetuximab soravtansine (Elahere®; AbbVie) [Prescribing Information]
Docetaxel (Taxotere®; Sanofi) [Prescribing Information]
Bevacizumab (Avastin®; Genentech/Roche) [Prescribing Information]

References
[1] Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, Hartmann LC. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008 Mar;108(3):619-26. doi: 10.1016/j.ygyno.2007.11.020. Epub 2008 Jan 28. PMID: 18222534; PMCID: PMC2707764.
[2] Coleman N, Yap TA, Heymach JV, et al. Antibody-drug conjugates in lung cancer: dawn of a new era? npj Precis Oncol. 2023;7:5. doi: 10.1038/.
[3] Salgia R. MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale. Mol Cancer Ther. 2017;16(4):555-565.
[4 ]Mo HN, Liu P. Targeting MET in cancer therapy. Chronic Dis Transl Med. 2017; 3(3): 148–153.
[5] Safaie Qamsari E, Safaei Ghaderi S, Zarei B, et al. The c-Met receptor: Implication for targeted therapies in colorectal cancer. Tumor Biol. 2017;39(5). doi: 10.1177/1010428317699118.
[6] Kim JH, et al. Clinicopathological impacts of high c-Met expression in head and neck squamous cell carcinoma: a meta-analysis and review. Oncotarget. 2017; 8:113120-113128.
[7] Macher-Goeppinger S, et al. MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker. Oncotarget. 2017; 8(1): 1046–1057.
[8] Kim JH, et al. Prognostic value of c-Met overexpression in pancreatic adenocarcinoma: a meta-analysis. Oncotarget. 2017; 8(42): 73098–73104.
[9] Kudoh S, et al. Significance of achaete-scute complex homologue 1 (ASCL1) in pulmonary neuroendocrine carcinomas; RNA sequence analyses using small cell lung cancer cells and Ascl1-induced pulmonary neuroendocrine carcinoma cells. Histochem Cell Biol. 2020;153(6):443-456.
[10] Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial. J Clin Oncol. 2024 Jun 6:JCO2400720. doi: 10.1200/JCO.24.00720. Epub ahead of print. PMID: 38843488.
[11] Sharma M, et al. Dose escalation results from a first-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors. J Clin Oncol. 2023;41(16_suppl):3015. Doi: 10.1200/JCO.2023.41.16_suppl.3015.
[12] Chandana SR, Garmezy B, Dowlati A, Sharma MR, Henner W, Robinson R, Hingorani P, Jeng E, Papadopoulos KP. 2029TiP – Phase I study of ABBV-706, an anti-SEZ6 antibody-drug conjugate, alone or in combination in adults with advanced solid tumors. Annals of Oncology (2023) 34 (suppl_2): S1062-S1079. 10.1016/S0923-7534(23)01926-9.
[13] Chandana SR, Choudhury NJ, Dowlati A, Chiang AC, Garmezy B, Kim JH, Averett Byers L, Ahn MJ, Min Kim T, Kim YC, Han JH, Bar J, Zha J, Henner W, Robinson R, Kohlhapp F,Hingorani P, Papadopoulos KP. First-in-human study of ABBV-706, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors. Journal of Clinical Oncology Volume 42, Number 16_suppl. 10.1200/JCO.2024.42.16_suppl.3001

Featured image © 2024 AbbVie Inc. All rights reserved. This study was first published on ADC Review | Journal of Antibody-drug Conjugates on September 11, 2024.

DOI 10.14229/jadc.2024.09.11.001 / DOI: 10.14229/onco.2024.09.11.010