Beyond Chemotherapy: The Rise of Precision Medicine and Targeted Therapy with ADCs

Pedro Valencia highlights AbbVie's progress with its ADCs platform for treating solid tumors in this exclusive interview and discusses the data presented at ASCO 2024. Valencia details how AbbVie is focusing on developing innovative ADCs targeting diseases like colorectal cancer (CRC) and non-small cell lung cancer, which despite recent innovations, still need new treatment options as survival rates remain low and patients often run out of options after multiple cycles of treatment.

Pedro Valencia Details AbbVie’s Innovative ADCs in Solid Tumors Presented at ASCO 2024

Pedro Valencia, Vice President, Solid Tumor Pipeline Strategy & Execution at AbbVie, discusses how AbbVie’s strategy is focused on replacing chemotherapy with targeted therapies such as Antibody-Drug Conjugates (ADCs), which may significantly increase survival and response rates across multiple cancers. These potentially transformative therapies, particularly ABBV-400 and ABBV-706, have demonstrated potential in improving clinical outcomes in early studies.

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Could you provide an overview of the key findings from AbbVie’s presentations on ADCs at ASCO 2024? How do these findings advance the current understanding of ADC therapies in solid tumors?

Pedro Valencia: At AbbVie, our primary focus is on targeting cancers with significant unmet medical needs, particularly those that are still being treated with chemotherapy regimens. Our objective is to design potentially transformative therapies that may elevate the standard-of-care for patients affected by these conditions. 

Diseases like colorectal cancer (CRC) and small cell lung cancer (SCLC) have been managed with the same conventional treatments for decades. Similarly, non-small cell lung cancer (NSCLC), despite innovations, typically offers patients a survival time of just a few years. Our strategy involves developing a pipeline centered around ADCs and immuno-oncology with innovative mechanisms of action aimed at transforming the treatment landscape for these diseases. 

At the recent ASCO Annual Meeting, we presented data from our ADC programs across three oral presentations and multiple other posters. Among these was a c-Met-targeted ADC, Teliso-V, with a monomethyl auristatin E (MMAE) payload specifically for NSCLC. Our pivotal Phase 2 data revealed significant improvements over standard chemotherapy in various metrics, such as overall response rate, duration of response, progression-free survival (PFS), and overall survival (OS).

Moreover, we demonstrated that targeting patients with high c-Met expression could further enhance outcomes, marking a significant step toward achieving our goal of transforming care in the second-line treatment setting, where only conventional chemotherapy was previously available.

The second highlight from our presentations was on CRC, where we introduced a next-generation, c-Met-targeted ADC, ABBV-400, equipped with a topoisomerase 1 inhibitor (Top1i) payload. CRC has historically been challenging to treat, often referred to as a novel therapy ‘graveyard’ in oncology due to the ineffectiveness of many new treatments evaluated in this setting. 

Our new ADC has shown promising increases in response rates and treatment duration, which is particularly notable in patients with overexpressed c-Met, where we observed response rates of nearly 20% across all patients and nearly 40% in those with high c-Met expression. Our last example pertains to SCLC, a notably aggressive disease with a five-year survival rate of 3%. Patients living with SCLC typically undergo multiple lines of therapy with limited success.

Our novel ADC, ABBV-706, targets SEZ6, a protein overexpressed in neuroendocrine neoplasms, including SCLC. In our Phase 1 dose escalation study, we observed a compelling overall response rate of 60% among SCLC patients and a disease control rate exceeding 90%, indicating significant benefits for nearly all treated patients. These advancements are pivotal in our mission to replace current treatments with more effective and targeted therapies, enhancing patient care across various hard-to-treat cancer types. 
Focusing on ABBV-400, the Phase 1 study results showed promising efficacy in heavily pre-treated metastatic CRC patients. Could you discuss the significance of these findings, particularly the observed ORR at different doses?

Pedro Valencia: In our Phase 1 study targeting advanced CRC—a disease where patients often survive less than a year—we’ve administered our drug, ABBV-400, to about 100 heavily pretreated patients. These patients, many of whom have exhausted on average four lines of therapy, typically see minimal benefits from conventional treatments, with response rates generally in the single digits. However, with ABBV-400, we’ve observed significantly quicker and more robust responses, even after just two treatment cycles.

In the dose escalation, at lower doses, we saw modest improvements, but at higher doses, such as 2.4 mg/kg, the response rate reached approximately 18%, and at 3 mg/kg, it increased to around 24%. This means about one in five patients responded to the treatment, a notable improvement over standard therapies. 

Particularly promising results were seen in patients with high c-Met expression, where response rates climbed to 38% at and above 2.4 mg/kg dose. These early results are encouraging and underscore the potential of continuing to advance this treatment in randomized controlled trials for CRC, aiming to significantly improve outcomes for this challenging condition.

ABBV-400 and Teliso-V both target the c-Met protein, while ABBV-706 targets SEZ6. Can you explain the rationale behind selecting these particular proteins as targets in your ADC development?

Pedro Valencia: When selecting protein targets for cancer therapy, we focus on three key criteria. Firstly, we prioritize proteins that are overexpressed in cancer cells but have limited expression in normal cells. 

Secondly, these proteins should be integral to the cancer growth cycle. Thirdly, our target proteins are those overexpressed in tumors with high medical needs and limited treatment options.

An example of such a protein is c-Met, which is involved in many cancers. Oncologists are probably more familiar with the MET gene, that in some patients gets amplified leading to the production of multiple copies of the gene. Patients with MET amplification, which is 1-3% across tumors, could be treated with small molecule Tyrosine Kinase Inhibitors (TKIs). 

With ADCs we are aiming to target protein c-Met that is overexpressed on the surface of the cells. c-Met protein’s overexpression is notably high, ranging from 25-50% in lung cancer and 30-70% in CRC, depending on the measurement approach. 

By targeting the c-Met overexpression, we address cancers like CRC and NSCLC, where the targeted cells depend on this protein for survival, yet it is minimally expressed in normal cells.

SEZ6 is a novel target, we identified SEZ6 as a surface-expressed SCLC target with broad expression in SCLC and minimal normal tissue expression. It is also overexpressed in neuroendocrine neoplasms, and subsets of prostate cancer, which are neuroendocrine-driven. This protein’s overexpression in specific tumor types and limited presence in normal cells makes it an exciting and promising target for our therapeutic strategies.

What can you tell us about the safety profiles of ABBV-400, ABBV-706, and Teliso-V based on the latest data? How are you addressing serious adverse events?
Pedro Valencia: Safety is a primary consideration for us – we not only want to improve the quantity but also the quality of life for patients. If we aim to replace chemotherapy, it’s crucial that the safety profile of our treatments is significantly better and more manageable than chemo. This is a consistent focus across our ADC therapies.

To date, across our ADC programs, we have seen manageable safety profiles. A critical safety aspect is the management of interstitial lung diseases (ILDs), which can differ between chemotherapy and ADCs. While ILD rates tend to be higher with chemotherapy, our objective is to maintain ILD rates within the range or lower than observed with other approved ADCs. We take these concerns seriously and have established an adjudicating committee to analyze every case of ILD. This committee helps us understand the underlying causes and informs strategies for better management in future trials.

How do the efficacy and safety profiles of these ADCs compare with current standard therapies?

Pedro Valencia: At ASCO, we presented three studies highlighting the efficacy of our therapies, notably the early-stage ABBV-400 and ABBV-706 and the more advanced Teliso-V. Across all three, we demonstrated elevated response rates compared to standard chemotherapy. Importantly, our safety profiles are not only manageable but often more favorable than those of conventional chemotherapy treatments.

With ADCs potentially replacing traditional chemotherapy, what implications do you foresee for treatment paradigms in cancers like NSCLC and colorectal cancer?

Pedro Valencia: In considering the future of disease treatment, particularly in replacing chemotherapy, the trend is shifting towards combining therapies. Currently, ADCs are mostly used as monotherapies, but increasingly, they are being tested in combination. The industry is moving towards combining ADCs with other modalities such as immuno-oncology therapies, like PD-1 and PD-L1 antibodies. 

This approach has shown promising results in transforming standard care, as seen in recent advances in bladder cancer and NSCLC. Additionally, we’re exploring combinations of ADCs with different mechanisms of action or targets, aiming to elevate treatment efficacy to new heights.

What are the next steps for clinical development of ABBV-400, ABBV-706, and Teliso-V? Are there upcoming trials?

Pedro Valencia: ABBV-400 is being evaluated in a Phase 1b basket study (NCT06084481) in advanced solid tumors, spanning multiple tumor types, including other gastrointestinal cancers, pancreatic, liver, head and neck and breast cancers - as a monotherapy and a Phase 2 study (NCT06107413) in second line metastatic CRC in combination with fluorouracil, folinic acid, and bevacizumab. These trials will inform our broader development strategy for ABBV-400. 

For ABBV-706, we are focusing on dose optimization and starting trials combining it with PD-1 inhibitors and chemotherapy. The results will potentially advance its use in SCLC and other neuroendocrine tumors. Teliso-V is progressing as well, now in a Phase 3 randomized control trial against docetaxel, which is proceeding successfully.

What long-term impacts do you anticipate these new ADCs will have on the treatment of advanced cancers? How does this align with AbbVie’s overall strategy in oncology?

Pedro Valencia: At AbbVie, we see the potential for ADCs to replace chemotherapy, especially in cancers like CRC, SCLC and NSCLC. Our strategy integrates ADCs with immuno-oncology to shift patients away from old treatments. By combining ADCs, which target cancer cells, with immuno-oncology approaches that activate T cells, we could see potentially synergistic effects. This combination could potentially lead to durable therapies or even cures for cancer. This innovative approach forms the core of our development strategy moving forward.

What are your reflections on the evolution of ADC technology and its future trajectory in oncology treatment? With the shift towards ADCs, how does AbbVie plan to position itself in the oncology market?

Pedro Valencia: We are enthusiastic about the new possibilities ADCs offer, especially as we’ve progressed in optimizing them with the right targets, linkers, and payloads to create a broad therapeutic window. 

This broader window allows for multiple dosing strategies and maximizes both efficacy and safety. The journey began with impactful ADCs in hematological malignancies and breast cancer, and now we are moving towards more refined ADCs with the capability to cater to various solid tumor types.

We’ve developed a versatile toolkit at AbbVie, which includes a variety of targets and payload types, such as MMAE, DM4, and Top1i ADCs, enhancing our ability to tailor therapies. This toolkit is pivotal in expanding our therapeutic scope to address diverse cancers, including ovarian cancer where we’re seeing promising results.

Additionally, we now have a first-in-class ADC, ELAHERE, in the market – for the treatment of platinum-resistant ovarian cancer. We are continuing to explore the potential of ELAHERE in the platinum-sensitive setting as well. 

As we shared at ASCO, our focus isn’t just on creating advanced therapies but also on broadening their application to improve outcomes for various patient segments. This strategic integration of new ADCs underscores our commitment to transforming cancer care.

About Author: Hüseyin Kandemir

As a medical journalist with over 20 years of experience, I have served as an Editor and Reporter for various magazines, newspapers, and online broadcasting platforms, consistently demonstrating a strong commitment to excellence in journalism. My specialization includes medical science, digital health, AI for health, data science, and biotechnology.