Effectively Targeting c-Met in Colorectal Cancer Is Becoming a Reality With Novel Approaches

John Strickler, MD

Early efficacy data observed with the novel c-Met–targeted antibody-drug conjugate (ADC) telisotuzumab adizutecan (formerly ABBV-400) in patients with colorectal cancer (CRC) have shown the potential to not only bring a c-Met–targeted agent into the CRC treatment landscape, but also an ADC to join fam-trastuzumab deruxtecan-nxki (Enhertu).

Several small-molecule agents targeting c-Met are already approved in non–small cell lung cancer (NSCLC), including capmatinib (Tabrecta),¹ tepotinib (Tepmetko),² and crizotinib (Xalkori),³ and cabozantinib (Cabometyx) holds an indication in renal cell carcinoma.⁴ However, when it comes to ADCs, telisotuzumab adizutecan represents one of the agents furthest along in development targeting c-Met. As of April 2024, 9 c-Met–targeting ADCs were under development in various phases of clinical studies, with additional preclinical studies ongoing.⁵

“We’ve seen ADCs now enter the clinic for multiple tumor types, but we’ve not yet seen an ADC with an approval specific to colon cancer,” John Strickler, MD, said in an interview with OncologyLive. “Right now, the only ADC we have approved for colon cancer is from the pantumor approval of trastuzumab deruxtecan for patients with HER2-positive cancers. But [with] this therapeutic strategy, this class [of ADCs], we are likely to see more therapies enter the clinic.”

Telisotuzumab adizutecan showed meaningful improvements in overall response rate (ORR) for patients who received the drug at a dose of 2.4 mg/kg or greater every 3 weeks in a first-in-human phase 1 study (NCT05029882).⁶ Recent data presented at the 2024 European Society for Medical Oncology (ESMO) Congress also showed the agent has activity in patients with advanced gastric/gastroesophageal junction adenocarcinoma.⁷

“We have a lot of experience with tyrosine kinase inhibitors [TKIs] and what we call the naked [monoclonal] antibodies in CRC, and unfortunately, nearly all that experience is unfavorable in that when we give patients these anti-MET therapies, the benefit, if it occurs at all, is fairly transient,” Strickler said. “One of the reasons for this is that c-Met expression or amplification can be heterogeneous. When you give these selective antibodies and TKIs, you’ll see brief, transient effects, but then the c-Met–negative clones will grow out and drive rapid resistance.”

Telisotuzumab Adizutecan Yields Promising Responses in CRC

Many advanced solid tumors have overexpression of c-Met, which can promote tumor progression and metastasis, and there are no approved therapies for patients with CRC and c-Met–overexpressing tumors.⁶

“Classically, we will see MET gene amplification and also overexpression of the protein after exposure to targeted therapies, particularly anti-EGFR therapies,” Strickler noted. “But interestingly, in the past couple of years, we’ve also seen signs that MET is important as a driver of resistance to other targeted therapies that have emerged in the CRC space, specifically anti-HER2 therapies and KRAS G12C inhibitors, which are now FDA-approved for the treatment of patients with metastatic CRC. We see this broadly as a driver of acquired resistance in addition to primary resistance to those therapies.”

In the first-in-human study, patients with BRAF wild-type, microsatellite stable (MSS) or mismatch repair–proficient (pMMR) CRC who experienced progression on prior therapies experienced an ORR of 18% when treated with the 2.4-mg/kg dose (n = 40) of telisotuzumab adizutecan. Patients treated at this dose level also experienced a median progression-free survival (PFS) of 5.3 months (95% CI, 3.8-5.9). Among those treated at the 3.0-mg/kg dose level (n = 41), the ORR was 24%, and the median PFS was 4.1 months (95% CI, 2.6-6.7). The ORR was lower in patients treated with the 1.6-mg/kg dose (n = 32) at 6%, with a median PFS of 5.1 months (95% CI, 2.8-6.8) observed (TABLE).⁶

Table. Efficacy of Telisotuzumab Adizutecan

in First-in-Human Study⁶

Further, the clinical benefit rates (CBRs) among patients who received the 1.6-mg/kg, 2.4-mg/kg, and 3.0-mg/kg doses were 75%, 78%, and 68%, respectively. The ORR was 16% among all patients (n = 122) treated in the trial, and the median duration of response (DOR) was 5.5 months (95% CI, 4.1-not evaluable [NE]).

“Focusing on gastrointestinal [GI] cancers, we’ve seen very promising initial results in patients with CRC. Interestingly, patients who have higher levels of c-Met expression appear to [derive an] even greater benefit,” Strickler said.

Patients with a c-Met expression level of at least 10% with 3+ staining intensity in the trial’s biomarker-positive population achieved an ORR of 37.5% when treated with 2.4 mg/kg or more of telisotuzumab adizutecan; the median PFS in this population was 5.4 months (95% CI, 2.7-6.9). For patients who received at least 2.4 mg/kg of telisotuzumab adizutecan but were biomarker negative, the ORR was 14%, and they experienced a median PFS of 4.5 months (95% CI, 3.8-5.9). Regardless of c-Met expression, all patients treated at this dose level experienced an ORR of 20%, with a median PFS of 4.6 months (95% CI, 3.9-5.4).

c-Met Targeting Proves Efficacious in Gastroesophageal Cancer

“So far, we feel like the safety, tolerability, and activity of this therapy are favorable and could have broad applications not just in CRC but in other GI cancers, in particular gastroesophageal adenocarcinoma. [Telisotuzumab adizutecan will] probably [have applications] beyond GI cancers as well,” Strickler said.

Promising antitumor activity was observed when telisotuzumab adizutecan monotherapy (n = 42) was administered in the dose-expansion portion of the phase 1 study to patients with advanced gastric and gastroesophageal junction adenocarcinoma. Patients achieved an ORR of 28.6% (95% CI, 15.7%-44.6%); 1 patient achieved a complete response. Additionally, the median DOR was 4.24 months (95% CI, 2.96-NE) and the agent elicited a CBR of 71.4% (95% CI, 55.4%-84.3%) in patients.⁷

Investigators also noted that the safety profile of telisotuzumab adizutecan in patients with gastric and gastroesophageal junction adenocarcinoma was generally consistent with what has been observed thus far in all patients treated with the agent. No grade 3/4 pneumonitis or interstitial lung disease events occurred.

“Although we’ve made a lot of progress with GI cancer [treatment], there’s still a lot of work to be done,” Strickler said. “One of the challenges is that once patients go through first- and second-line therapies, response rates drop off, and PFS for the approved agents is rather short. There are some promising signals, particularly among patients with higher levels of c-Met expression, [showing] that [telisotuzumab adizutecan] can generate higher response rates than the current standard of care [SOC]. It can potentially drive longer PFS, though we’ll need to see that validated in prospective studies, but it also raises the question of whether this is a therapy that’s so active it [may] need to be brought into earlier lines of therapy in combination with other cytotoxic chemotherapy.”

Delving Into Safety With the ADC in CRC and Gastric Cancers

Regarding safety with telisotuzumab adizutecan, hematologic treatment-emergent adverse effects (TEAEs) were dose dependent, as investigators noted the frequency and severity increased with higher doses. In the CRC population, patients in the 1.6-mg/kg, 2.4-mg/kg, and 3.0-mg/kg dose groups experienced grade 3 or higher TEAEs (38% vs 73% vs 88%); the most common grade 3 or greater hematological TEAEs were anemia (13% vs 33% vs 54%), neutropenia (6% vs 20% vs 32%), and thrombocytopenia (0% vs 8% vs 17%).⁶

TEAEs also led to treatment discontinuation in 25 patients (20.5%), resulting from anemia (n = 4), pneumonitis (n = 3), and febrile neutropenia (n = 2). Events leading to discontinuation were considered related to telisotuzumab adizutecan in 13 patients.

Up Next: Telisotuzumab Adizutecan vs SOC in CRC

“The main next step for telisotuzumab adizutecan [includes] prospective validation against SOC therapies [with] larger randomized trials that can validate that patients have improved survival, PFS, response rates, and tolerability as compared with the current SOC. We are now in the development [stage of] these randomized trials,” Strickler said.

A phase 2 randomized trial (NCT06107413) was initiated in November 2023 and has 19 patients with metastatic BRAF V600 wild-type, MSS or pMMR CRC enrolled as of April 23, 2024, who will receive telisotuzumab adizutecan in a combination-therapy approach. The safety lead-in portion of the study will enroll 30 patients to receive telisotuzumab adizutecan in combination with 5-fluorouracil and folinic acid plus bevacizumab (Avastin) at various doses. Stage 2 of the study, the dose optimization part, will enroll 176 patients in 4 investigational cohorts examining the investigational regimen at the low dose administered every 4 weeks, high dose administered every 4 weeks, low dose administered every 2 weeks, and high dose administered every 2 weeks. Additionally, there will be a fifth SOC cohort with leucovorin, fluorouracil, and irinotecan plus bevacizumab administered every 2 weeks.⁸

“CRC in particular is notorious for having molecular heterogeneity, where MET amplification [will] go together with other variants; for example, KRAS mutations, NRAS mutations, or BRAF alterations,” Strickler said. “Even when you give a targeted therapy, you may see that those other variants can drive rapid resistance as well. The advantage of an ADC is it only needs expression to enter the cell; if the patient has tumor cells that will drive resistance to the targeted therapy, it won’t matter because the drug will still get in and release its toxic payload to that tumor.”

In addition to the promise demonstrated with ADCs targeting c-Met in CRC, NSCLC data have also shown the efficacy of this approach. Findings from the same phase 1 study evaluating telisotuzumab adizutecan monotherapy in various patient populations were presented at the 2024 ESMO Congress and revealed that patients with EGFR wild-type nonsquamous NSCLC treated with telisotuzumab adizutecan (n = 48) experienced an ORR of 47.9%. Patients experienced a median PFS of 6.9 months (95% CI, 5.4-7.3). As in the CRC population, responses were enriched in patients with higher c-Met protein expression. In patients with immunohistochemical staining of 3+ on at least 50% of tumor cells, the ORR was 77.8%.⁹

Additionally, AbbVie, the drug manufacturer of another c-Met–directed ADC, telisotuzumab vedotin (Teliso-V), noted that they plan to submit Teliso-V to the FDA for accelerated approval as a monotherapy for the treatment of patients with previously treated c-Met-overexpressing, EGFR wild-type nonsquamous NSCLC; the company anticipates a decision in 2025 for the c-Met targeted agent.¹⁰ In this patient population, the ORR was 34.6% (95% CI, 24.2%-46.2%) among patients with c-Met–high disease (n = 78) treated with Teliso-V, and 22.9% (95% CI, 14.1%-33.4%) among patients with c-Met–intermediate expression (n = 83).¹¹

“[Telisotuzumab adizutecan] is an active therapy that looks very promising for our patients with GI cancers and also for patients with MET-amplified tumors,” Strickler said. “It’s a therapeutic strategy that is currently under development [and] needs validation but so far looks very promising.”

References

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3. Xalkori. Prescribing information. Pfizer; 2023. Accessed September 10, 2024. bit.ly/3ATXc2u
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10. AbbVie showcases advancement of solid tumor pipeline at ESMO 2024, with new data in tumor types with high unmet needs. News release. AbbVie. September 9, 2024. Accessed September 10, 2024. bit.ly/4dV4j9L
11. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC: primary analysis of the LUMINOSITY trial. J Clin Oncol. 2024;42(suppl 16):103. doi:10.1200/JCO.2024.42.16_suppl.103