🌐 Also available in: 🇩🇪 Deutsch
Original source: World Medical Innovation Forum
This video from World Medical Innovation Forum covered a lot of ground. Streamed.News selected 8 key moments and summarises them here. Everything below links directly to the timestamp in the original video.
Understanding the trade-offs between drug efficacy and patient tolerability is crucial in cancer treatment. This discussion highlights why new, effective therapies aren't always immediately adopted as first-line options.
Rybrevant's Efficacy in Lung Cancer Countered by Significant Toxicity
The EGFR MET bispecific agent Rybrevant (Amivantamab) shows clear activity in EGFR-mutated lung cancer, but its significant toxicity profile has led to clinician hesitation for its frontline use. Despite demonstrating a survival benefit in the frontline MARIPOSA trial, experts note that its adoption has been less robust compared to TKI-chemotherapy combinations, which are perceived as more tolerable for patients.
This hesitancy is further compounded by recent data from the FLAURA2 trial, which showed survival benefits with chemotherapy combinations. Clinicians currently lack biomarkers to effectively identify patients who might benefit most from Rybrevant without experiencing severe side effects, leading to its common reservation for later-line therapy.
"I think as a field there has been some hesitation to use Amivantamab frontline just because of the… duration of time that patients have that are on that therapy and the toxicities that go along with it."
Clinicians Prioritize Efficacy and Safety Over Cost for New Cancer Drugs
Medical professionals in the U.S. healthcare system primarily prioritize drug efficacy and patient safety when selecting cancer treatments, even with the potential introduction of biosimilar versions of established drugs like Keytruda. Panelists noted that clinicians are not incentivized to choose cheaper options if they perceive another treatment as superior in effectiveness and tolerability.
This dynamic suggests that the mere availability of lower-cost biosimilars may not significantly alter the adoption rates of novel, more expensive bispecific therapies if those therapies demonstrate clear clinical advantages. The focus remains on patient outcomes rather than economic factors in the prescribing decision-making process.
"In the U.S. the clinician doesn't feel the cost necessarily, right? And so we're not incentivized to choose the cheaper option. We're going to go with what we think is the better, from an efficacy and safety standpoint."
RAS Pathway Inhibitors Show Promise but Lack Desired Durability
The development of G12C specific inhibitors for the RAS pathway represents a significant breakthrough in cancer treatment, targeting a previously undruggable mutation prevalent in a quarter of lung cancer patients. However, panelists expressed disappointment with the current level of activity, noting that response rates and durability fall short of the 60-70% response rates and multi-year survival observed with other targeted lung cancer treatments.
This calls for continued research into next-generation approaches, including molecular glue assets and pan-RAS inhibitors, to enhance the response and durability of these therapies. Improving outcomes for patients with RAS-mutated cancers remains a critical area of focus, aiming to expand treatment beyond just G12C mutations to other altered alleles.
"The G12C specific inhibitors were a huge advance, right? It used to be that RAS was undruggable. This was not a target. And the fact that in lung cancer where that's a quarter of patients who have RAS mutations... the fact that you can target that is a huge advance."
Trop-2 ADCs Face Tolerability Hurdles in Frontline Lung Cancer
Trop-2 antibody-drug conjugates (ADCs) like Gilead's Trodelvy and AstraZeneca's Dato-DXd show activity in lung cancer, but their tolerability in the frontline setting remains a significant concern. Clinicians are hesitant to use therapies with substantial upfront toxicity, especially when current standard-of-care regimens, such as IO or chemo-IO combinations, are generally well-tolerated.
For widespread adoption in frontline lung cancer, Trop-2 ADCs must demonstrate clear overall survival benefits in Phase 3 trials and ideally be supported by robust biomarkers that identify patient subsets most likely to benefit. Without these, the high bar set by existing, better-tolerated treatments will likely limit their initial use.
"As you're starting treatment for lung cancer, you definitely want the efficacy, but to hit people with a ton of toxicity upfront is actually pretty challenging."
Personalized vs. Off-the-Shelf mRNA Vaccines for Cancer
The future of cancer vaccines is exploring both personalized and off-the-shelf mRNA technologies. Personalized vaccines, such as Merck and Moderna's V940, offer high immunogenicity by targeting individual tumor characteristics but present significant logistical challenges due to their customized production. In contrast, off-the-shelf mRNA vaccines targeting shared tumor-associated antigens are more logistically feasible but may offer lower immunogenicity.
Panelists noted that the adjuvant setting, where there is more time for development post-surgery, appears to be the most suitable context for personalized, tumor-informed vaccines. This allows for recovery time and reduces the urgency seen in neo-adjuvant settings, making personalized approaches more practical.
"In the adjuvant space there's time... So in my mind, I think that's actually an ideal time to think about, you know, taking the time to develop something that may be tumor informed."
Clinical Meaningfulness of PD1 VEGF Bispecifics Debated Despite Patient Benefit
A 0.8 overall survival (OS) hazard ratio for PD1 VEGF bispecifics, such as the data from the HARMONIA study showing a 0.79 ratio, is considered clinically meaningful by medical oncologists, despite investor disappointment. Panelists emphasized that this outcome represents a tangible benefit for patients, especially in later lines of therapy where options are limited.
The investment community's higher expectations for more dramatic hazard ratios underscore a disconnect between financial metrics and clinical reality, where even incremental survival gains are significant for patients. Clinicians note that historical ASCO guidelines suggest such ratios are sufficient for adoption, highlighting the evolving, often spoiled, expectations in cancer treatment outcomes.
"When you look at ASCO guidelines of what has historically been deemed worthy of of implementing it, you know, 0.78 is in the range of of what we would expect."
Amivantamab Deemed Too Toxic for Adjuvant Lung Cancer Treatment
Panelists concluded that amivantamab's toxicity profile makes it unsuitable for adjuvant use in lung cancer, where patients are potentially cured and have a lower tolerance for side effects. In the adjuvant setting, even relatively mild toxicities from drugs like osimertinib are poorly accepted, as patients prioritize quality of life given their curative intent.
However, a short-course neoadjuvant approach with amivantamab sparked mild intrigue among clinicians, acknowledging current struggles in that space and the need for new strategies. While still potentially toxic, the shorter duration pre-operatively might be more tolerable, offering a potential avenue for its use.
"I would be very blunt. I would see no future for that as an adjuvant. It's just too toxic, and I think that the benefit would be incremental."
Early RAS Inhibitor Data with Keytruda Shows Promise but Requires Caution
Early phase one data on a RAS inhibitor combined with Keytruda in frontline lung cancer, specifically showing an 86% objective response rate and 100% disease control rate in high PD-L1 expressors, appears encouraging. However, panelists cautioned against direct comparison to registrational studies, citing significant patient selection bias in early-phase trials where enrolled individuals typically have better disease biology and can afford to wait for treatment.
This highlights the need for dedicated, individual drug studies to thoroughly evaluate the combination of RAS inhibitors with PD1 therapies, as not all combinations prove compatible due to issues like hepatotoxicity. The path forward involves rigorous testing to confirm efficacy and safety across broader patient populations.
"It's encouraging, but I don't think we can compare that to then registrational phase three studies and say, 'Hey, this is going to be that, you know, this is the next thing.'"
Summarised from World Medical Innovation Forum · 41:15. All credit belongs to the original creators. World Medical Innovatio Forum summarises publicly available video content.
