Why Leonardo da Vinci would have loved ASCO 2024
By: Caitlin Moore, Matt Furlow, Dave Kriesman, Stephanie Spies and Christina Corridon
Alongside 44,000 other attendees, my colleagues and I (on behalf of ZS), participated in this year’s annual meeting of the American Society of Clinical Oncology (ASCO), themed “Art and Science of Cancer Care: From Comfort to Cure.” The emphasis on patient well-being at the heart of cancer care was evident throughout the conference. Amid remarkable data advancements, our team was impressed by the focus on personalized treatments to increase response likelihood and reduce toxicity, practical management approaches and the drive for equity, often empowered by AI solutions. With over 6,600 abstracts, established pharmaceutical companies led in data volume (see Figure 1 below).
Figure 1: Number of scientific abstracts by company (Source: ZS analysis)
We took on the daunting task of sorting through the data that clearly reflected the core themes: the science of cancer care and the commensurate contribution of the art of cancer care. When considering the balance between art and science, we’re reminded of Leonardo Da Vinci, who skillfully combined both. Just as his classical work, the Vitruvian man, embodies the ideal balance of art and science, this approach illustrates an optimal practice of medicine.
The science of cancer care: Clinical advancements and innovations
Across therapeutic platforms, ASCO continues to be a stage for revealing meaningful, innovative developments. A few innovations that caught our attention are highlighted below:
Cancer vaccines: The forthcoming mRNA-4157/V940+ Keytruda in adjuvant melanoma has shown strong efficacy with data from their Phase 2b KEYNOTE-942, indicating a 2.5-year recurrence-free survival rate of approximately 75%. Building on these foundational results, the Phase 3 results are highly anticipated, with rapid trial enrollment of 1,000 patients for the Phase 3 trial.
Cell therapy: Cell therapies have found a stronghold in hematologic malignancies but have struggled to transition to solid tumors, with the exception of Amtagvi’s approval in melanoma and afami-cel’s recent BLA in synovial sarcoma. However, the next generation of CAR-Ts engineered against novel targets (GPC3, CLDN18.2) shows promising results. Objective response rates (ORRs) for these new targets reached between 50–60%, which is trending towards the efficacy we have grown accustomed to seeing with CAR-Ts in hematological malignancies.
Antibody drug conjugates (ADCs): With 30 unique studies in ADCs presented at ASCO, there is a lot of innovation to cover. The late-breaking abstract of Destiny Breast-06 revealed a new categorization of HER2 expression, HER2-ultralow (IHC 0 with membrane staining). Despite a small sample size (~150 patients), the clinical response of patients was similar to the HER2-low group, showing a benefit for patients that had any level of expression and broadening our understanding of ADC efficacy across a well-known biomarker. Beyond established molecular targets, numerous studies investigated novel targets. Firstly, the LUMINOSITY trial provided a look at the c-MET targeting ADC Teliso-V. This study examined c-MET overexpression in EGFR wildtype NSCLC, as well as the response to monotherapy Teliso-V, which was ~35% ORR in high cMET expressers. In earlier phase clinical trials, there were a wealth of novel targets: ABBV-706 examining seizure-related homolog protein 6 (SEZ6) in advanced, difficult to treat tumors; M9140 highlighting a novel linker and targeting CEACAM5 for heavily pre-treated CRC patients; and DS-3939a targeting tumor associated mucin (TA-MUC1), that is overexpressed in most epithelial-based cancers.
Immunotherapies: The next generation of immunotherapies is attempting to emerge from the shadow of Keytruda. The evening before ASCO kicked off, Summit Therapeutics revealed data for their asset ivonescimab vs Keytruda in a China-based trial population (HARMONi-2). While the FDA awaits a US-based trial population before approval, the progression-free survival improvement in low PD-L1 expression sent the Summit shares soaring and raised $200 million after an institutional investor purchased roughly 22 million shares of company stock.
Precision medicine: Many platforms rely on precision targeting of molecular alterations for cancer patients. Despite advancements made in precision oncology, this area remains active as we gain deeper understanding of the tumor microenvironment and genetic drivers of cancer. The ADCs were a notable example of this deepening understanding across multiple data readouts:
○ In EVOKE-01 sacituzumab govitecan (Trodelvy), a TROP2 targeting ADC was examined retrospectively vs. docetaxel in 2L+ NSCLC. Interestingly, PD-1 non-responders and patients with genomic alterations did meaningfully better with sacituzumab govitecan, providing coverage in a patient population with high unmet need. In a similar vein, enfortumab vedotin (Padcev) was determined to be active regardless of nectin-4 expression, but nectin-4 gene amplification is predictive of response.
AI in Cancer Care: AI solutions were also prevalent at ASCO, with more than 30 oral sessions on AI in oncology. Notably, in the keynote speaker series on May 31, Dr. Jonathan Carlson (Microsoft Health) highlighted the promise of generative AI empowering oncologists– pressure-testing treatment options, optimizing workflow management and creating first drafts of documents such as treatment plans. One tangible example of this technology improving patient experience was in colorectal cancer (CRC) patients, where an AI Patient navigator (My Eleanor) contacted patients who had canceled or missed their colonoscopies. Over 8 months, 58% of patients accepted a live● transfer after interacting with the AI tool. This resulted in a near doubling of patients completing their colonoscopies.
The art of cancer care: Optimizing care delivery and equitable access
The art of cancer care continues to evolve, often assisted by advancing technology and translating scientific advancements into how the patient is impacted. Even though targeted treatments have been a feature of oncology treatment since the 1990’s, we are only just beginning to realize the full potential of precision medicine — and expanding what precision means for patients. This manifested in several key topics (discussed here and in Figure 2 below):
Better targets and clearly defined patient subpopulations to maximize therapy potential: Again, the ADCs were a notable example of this theme coming to life, as discussed above. That said, we also need to go beyond simply measuring expression of a target in terms of positivity or percentage of cells staining positive; we need to characterize spatial and temporal heterogeneity for each individual patient. A notable example of this need is in TROP2 (trophoblast cell surface antigen 2) targeting ADCs, where variable responses have been seen across levels of expression in numerous tumor types (TROPiCS-02, ASCENT, TROPHY). Understanding what is contributing to efficacy across expression will help optimize patient selection for TROP2s.
Identifying optimal sequencing: Not only can we learn more about the targets themselves, we can also learn about mechanisms of resistance. ADC resistance can come from target (mutation, downregulation, etc.), payload or internalization. As we understand more about the mechanisms of resistance, this translates into how this information is clinically applied, namely through sequencing. This topic was highlighted in breast cancer this year, where the latest data in sequencing ADCs was discussed. One example is a forthcoming trial TRADE-Dxd, where a cross-over design will be used to identify if sequence and disease progression is impacted by receiving Enhertu or Dato-Dxd (datopotamab deruxtecan).
Utilizing ctDNA and MRD to guide treatment intervention and cessation: A great example of this was the MRD2STOP trial, that found a higher threshold for myeloma MRD through enriching existing samples. They identified a meaningful 3 year “MRD Free Survival” in ~80% of patients with a higher threshold of MRD detection (10–7). However, the promise of ctDNA has not quite translated into solid tumors (yet), but the amount of evidence is mounting for prognosis and treatment discontinuation. For example, in the ADAURA trial, MRD predicted disease recurrence by roughly 5 months. In a dedicated session on the use of ctDNA in breast cancer titled “Are we there yet?”, the answer was yes, with caveats. Oncologists must find a fit-for-purpose assay, as the capabilities and sensitivities will vary widely — and their current expense can limit their clinical use.
Figure 2: Precision medicine topics at ASCO 2024 (Source: ZS analysis)
Beyond increasing the level of specificity of treatment selections, a critical eye was cast on the approach to treatment, revealing multifactorial attempts to improve patient experience:
Dosing frequency and duration matters to balance efficacy with side effect potential across many tumors:
o DREAMM-7 and -8 are highly positive studies that should re-introduce Blenrep to 2L+ MM and a crucial part of that success was optimizing dosing. Counterintuitively, ‘less is more’ here as less frequent dosing seems to have resulted in lower rates of ocular AEs while maintaining efficacy.
o Despite receiving a standing ovation for the LAURA trial, the primary question on the audience’s minds was–do patients truly need therapy for 3 years to achieve these outcomes? Are we over-treating patients? The answer is unclear, but the hope is we can use MRD/ ctDNA to offer treatment holidays in the future.
Treatment holidays in immune checkpoint inhibitor administration: A case-based panel discussed what the latest evidence supports across IO therapy and identified that treatment cessation is conceptually sound, but hard to enact with a real patient. For example, in lung cancer, panelists discussed real world data that revealed 80% of patients are receiving treatment beyond 2 years — despite numerous retrospective analyses that offer no benefit beyond 2 years if there has been no progression.
Better routes of administration: Amivantamab shared late-breaking data on its subcutaneous formulation, demonstrating not only non-inferior ORR to intravenous administration, but also surprising benefits for those who received subcutaneous Rybrevant in duration of response, PFS and OS along with an improved safety profile.
Learning from ASCO 2024
In the intricate dance between art and science within medicine, particularly in oncology, achieving equilibrium is no small feat. ASCO’s unwavering commitment to harmonizing these elements is pivotal for progress. Balancing pragmatism, evidence, compassion and equitable access, we echo Da Vinci’s timeless wisdom: ‘Medicine is the restoration of discordant elements.’
