Key Data Insights from ASCO 2026: Remarkable Breakthroughs in RET/ALK/KRAS Targeted Therapies

Overview

This report is a summary of the KOL breakfast meeting organized by Bernstein during ASCO 2026, inviting leading lung cancer clinician Fred Hirsch to systematically review key clinical data presented at the conference on early and advanced treatments for non-small cell lung cancer (NSCLC). From a real-world clinical perspective, it evaluates the clinical value, implementation challenges, and commercial potential of emerging therapies.

Core views

The report’s core view focuses on the deepening evolution of molecular targeted therapies. In the RET-positive early-stage NSCLC field, the LIBRETTO-432 study showed that selpercatinib (Eli Lilly) adjuvant therapy achieved an astonishing HR of 0.17, setting a new benchmark for early targeted treatment. However, about 70% of RET+ patients are never-smokers, making them difficult to include in existing lung cancer screening programs, thus low detection rates remain the biggest implementation barrier. For the ALK pathway, lorlatinib (Pfizer) failed to reach median PFS even after 7 years of follow-up in the CROWN study, setting an extremely high standard. Meanwhile, Nuvalent’s fourth-generation ALK inhibitor achieved a response rate of ~26% in patients resistant or intolerant to lorlatinib, precisely filling the treatment gap for patients with neurological toxicity or comorbidities. The KRAS space is becoming the next major battleground—divarasib’s data in first-line KRAS G12C treatment have been described as ‘potentially practice-changing,’ and Revolution Medicines’ G12D and pan-RAS inhibitors (ON) are progressing rapidly, far exceeding market expectations. In the TROP2 direction, Sacituzumab Tirumotecan (Sac-TMT) showed more compelling data than other similar ADCs in NSCLC, yet its ‘population-wide strategy without biomarker selection’ clashes fundamentally with Dr. Hirsch’s philosophy as a biomarker researcher. Additionally, although the HARMONi-6 study for squamous NSCLC (ivonescimab) showed an encouraging OS HR of 0.66, since it was conducted only in the Chinese population, Dr. Hirsch made it clear that he would not prescribe based solely on this HR value and insisted on waiting for OS data from the global Phase III HARMONi-3 trial.

Analysis framework

The report adopts a 'clinician-first perspective' as its analytical framework, reevaluating cutting-edge clinical trial data within real-world clinical settings. Analysts did not stop at statistical significance (such as HR values), but delved deeper into the clinical accessibility behind the data: how patients are identified (e.g., the dilemma of RET+ screening), how treatment is sustained (e.g., the low reliability of ctDNA monitoring in early-stage patients), and how drugs are tailored to individual patients (e.g., the impact of age, comorbidities, and tumor location on the bleeding risk of VEGF inhibitors). This analytical approach goes beyond purely academic interpretations, directly addressing the core bottlenecks of commercialization—from 'effective' to 'available' to 'willing to use.'

Methodology notes

• Industry/Industrial Analysis FrameworkSupply-demand framework

  The industry’s core contradiction lies in the dynamic match between supply-side (new drug development progress) and demand-side (unmet clinical needs).

  The report repeatedly emphasizes 'unmet needs,' such as patients intolerant to lorlatinib and those missed by RET+ early screening. It is precisely by identifying these rigid clinical gaps that we can assess the true market space and clinical adoption speed of new drugs.

• Industry/Industrial Analysis FrameworkVolume-price decomposition

  Separating clinical value (volume) from commercial value (price).

  For example, although Sac-TMT has excellent efficacy data, its pricing power and reimbursement pathways remain uncertain due to the lack of companion diagnostic strategies. Meanwhile, although HARMONi-6 showed good OS data, its global pricing foundation is weak because of the limited patient population.

• Company Fundamentals and Financial FrameworkProfit Quality Analysis

  Focusing on the substantive impact of clinical data on product lifecycle and revenue sustainability.

  The report specifically pointed out that lorlatinib’s ‘duration of therapy is likely to be impressive,’ suggesting its long-term medication attributes will bring stable cash flow. Meanwhile, Nuvalent targets a ‘niche’ market, solving specific subgroups’ problems through differentiation, thus building high barriers and strong pricing power.

Asset mapping & comparison

Structured mapping from thesis to named assets (strengths, weaknesses, peers, risks).

• LLY.US (Eli Lilly)

  Core holder of selpercatinib (RET inhibitor); LIBRETTO-432 data established its leadership position in early targeted therapy.

  Strengths

  Good CNS penetration, mature commercialization channels already established, solid clinical data.

  Weaknesses

  Low detection rate of RET+ patients limits the speed of early market expansion.

  Comparison

  Compared to China’s similar RET inhibitor (lunbotinib), it has global clinical development capabilities and advantages in FDA approval pathways.

  Risks

  After approval for early-stage NSCLC indication, real-world screening coverage may fall short of expectations.

• NUVL.US (Nuvalent)

  Developer of fourth-generation ALK inhibitors, focusing on the clear unmet need of patients intolerant or resistant to lorlatinib.

  Strengths

  Clinical data directly addresses pain points (~26% ORR), clear R&D path, high institutional shareholding (>1% held by AB and affiliates).

  Weaknesses

  Relatively narrow market size, facing cultural inertia from lorlatinib’s long-term dominance.

  Comparison

  Unlike lorlatinib’s ‘broad-spectrum efficiency,’ Nuvalent takes a ‘precise substitution’ route, giving it higher bargaining power in specific subgroups.

  Risks

  If the final OS data from the HARMONi-3 global Phase III trial fall short of expectations, its entry into mainstream guidelines will be delayed.

• RVMD.US (Revolution Medicines)

  Developer of pan-RAS inhibitors (ON series), covering KRAS G12D and broader RAS mutation spectrum.

  Strengths

  Most comprehensive RAS-targeting portfolio, positive early-stage data, aligning with the consensus that 'KRAS is the next major battleground.'

  Weaknesses

  Early-stage clinical validation of targets like G12D is still underway, and competitors (such as Mirati) are also moving quickly.

  Comparison

  Compared to divarasib’s (G12C single-point breakthrough), Revolution bets on a broader RAS spectrum, balancing risks and rewards.

  Risks

  Off-target toxicity or lower efficacy of pan-RAS inhibitors compared to G12C-specific inhibitors.

Key data

• LIBRETTO-432 (selpercatinib)HR = 0.17Adjuvant therapy for RET+ early-stage NSCLC, reducing event occurrence risk by 83%, the strongest signal to date in this field.
• CROWN Study (lorlatinib)Median PFS not yet reached after 7-year follow-upCompared to the 6-7 month median survival of ALK+ patients 20 years ago, this highlights a revolutionary advance in treatment paradigms.
• Nuvalent ALK Inhibitor~26% response rateIn patients relapsed or refractory to lorlatinib, targeting special populations with neurotoxicity or comorbidities.
• HARMONi-6 (ivonescimab)OS HR = 0.66China Phase III study for squamous NSCLC, but the maximum patient age is 75, and inclusion criteria are descriptive rather than analytical.

Impact & implications

The report argues that lung cancer is accelerating its shift from an 'acute lethal disease' to a 'manageable chronic condition,' with some molecular subtypes achieving survival rates of 7-10 years. For pharmaceutical companies, this means product success no longer depends solely on single-time efficacy, but on long-term medication safety, patient adherence management, and the construction of a survivorship ecosystem. For payers, chronic disease treatment will reshape health insurance negotiation logic—from payment per course to payment per year or per quality of life. For investors, companies truly capable of providing 'full-cycle solutions' (diagnosis + treatment + support) will gain valuation premiums.

Risks

• The final OS data from the HARMONi-3 global Phase III trial did not reach statistical significance, severely undermining ivonescimab’s commercial prospects.
• Long-term low prevalence of RET+ patient screening leads to actual prescription volumes below expectations after LIBRETTO-432 approval.
• TROP2 ADC drugs (such as Sac-TMT) may face Medicare denial or restricted clinical use due to the lack of biomarker guidance.

What to watch

• HARMONi-3 trial OS interim analysis results (expected to be released in the second half of 2026)
• Updated long-term follow-up data from the CROWN study and progress on lorlatinib’s real-world resistance mechanisms.
• Progress on Sac-TMT’s companion diagnostics (CDx) development in NSCLC and regulatory communication status.