Key outcomes of ASCO24

Our experts were pleased to join #ASCO24 this year. Prior to the congress, we shared some key themes and questions we expected to be raised (Figure 1). We are now summarizing the key insights and takeaways on these modalities from ASCO 2024.

Figure 1

Antibody drug conjugates: Redefining cancer treatment

• Patient sub-populations are being characterized to unlock the potential of ADCs
  • Biomarker correlate studies now becoming an integral part of early clinical development e.g. SEZ-6 correlate with efficacy in SCLC, neuroendocrine tumors (ABBV-706)
  • Learnings from retrospective analysis of failed trials will help optimize future studies E.g. Sacituzumab govitecan in EVOKE-01 demonstrated most benefit in mNSCLC patients with PD/SD to last PD-1i therapy
• Enhertu is changing the DESTINY of breast cancer patients, though…
  • What is the physician perspective on the need for a Dx to identify 85-90% Enhertu eligible patients progressing on ET?
  • What are the efficacy vs safety/convenience trade-offs? Pneumonitis, nausea with an IV treatment?
• Next gen drug conjugates target a better therapeutic index through reduced off-target effects
  • The novel linker/conjugation chemistry of nectin-4 bicycle toxin conjugate (BT-8009) and ADCs (9MW2821 and CRB-701) demonstrated faster clearance of toxin conjugates and reduced exposure to it, though yet to be seen whether this translates into similar or even better efficacy than enfortumab vedotin

Radiopharmaceuticals: ‘Hotspot’ of attention

• The success of beta-emitting radiopharmaceuticals is paving the way for wider use of alpha-emitters
  • Innovative trial designs aim to mitigate toxicity issues with double strand break inducing alpha particle emitters e.g. JNJ-6420 targeting hK2, tested cumulative dose cap and an adaptive dosing schedule to address ILD and thrombocytopenia in mCRPC
  • Next-generation alpha emitters are competitively positioned vis-à-vis beta-emitters. e.g RYZ-01, SSTR2 alpha-emitter in post Lu177 labelled SSA exposed neuroendocrine tumors, albeit with a response, ACTION-1
• ctDNA analysis is generating hypothesis-driven evidence to identify predictive biomarkers for radiopharmaceuticals
  • Potential biomarkers can identify patients that may not derive optimal benefit. E.g. 8q amps, AR amps, TP53 deleterious mutations predictive of sub-optimal benefit with Lu 177 vipivotide tetraxetan [PSMAfore study]
• Synergistic radiopharmaceutical combinations to address persisting unmet needs
  • Combining immunotherapy with radiopharmaceuticals are expected to have strong synergy, though clinical validation pending E.g. Will Lu177 conjugated CA-IX antibody + PD-1i + TKI lead to expected incremental CR in RCC patients?

Bispecifics: Valuable addition to the treatment arsenal in solid tumors

• Bispecifics: Overcoming their own limitations
  • Sub-populations of CNS mets patients may derive benefit with bispecifics, known to be associated with neurotoxicity – stable and active CNS mets, smaller brains mets lesions e.g. Tarlatamab sub-group analysis in SCLC patients (DeLLphi-301) was effective irrespective of treated and stable brain mets
  • Sub-cutaneous route of administration likely to provide a strong competitive advantage to bispecifics E.g. sc amivantamab demonstrated non-inferior efficacy to the IV version, including reduced infusion related reactions, venous thromboembolism besides patient convenience (PALOMA-3)
• New targets, new hope in underserved patients
  • EGFR X LGR5 bispecific holds potential to be transformational in mHNSCC given relevance of EGFR pathway and LGR5 internalization leading to EGFR degradation E.g. Petosemtamab with pembrolizumab has demonstrated impressive 67% RR in L1 mHNSCC patients and moving into registrational studies

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References:

1. Dato-DXd, ICARUS-LUNG01, Abs#8501, ASCO 2024
2. Sacituzumab govitecan, EVOKE-01, Abs#LBA8500, ASCO 2024
3. T-DXd, DESTINY-Breast06, Abs#LBA1000, ASCO 2024
4. ABBV-706 (SEZ6 ADC), NCT05599984, Abs#3001, ASCO 2024
5. 9MW2821 (Nectin-4 ADC), NCT05216965, Abs#3013, ASCO 2024
6. SYS6002 (Nectin-4 ADC), ChiCTR2200066256, Abs#3151, ASCO 2024
7. BT8009 (Nectin-4 BTC, NCT04561362), BT5528 (EphA2 BTC, NCT04180371), Abs#3088, ASCO 2024
8. Amivantamab (EGFR X MET BiSp), PALOMA-3, Abs#LBA8505, ASCO 2024
9. Tarlatamab (DLL3 X CD3 BiSp), DeLLphi-301, Abs#8015, ASCO 2024
10. Petosemtamab (EGFR X LGR5 BiSp), NCT03526835, Abs#6014, ASCO 2024
11. PLUVICTO, PSMAfore (ctDNA), Abs#5008, ASCO 2024
12. JNJ-69086420 (²²⁵Ac labeled hK2 Ab), NCT04644770, Abs#5010, ASCO 2024
13. RYZ101 (Ac225 RLT), ACTION-1, Abs#236, ASCO 2024
14. 177Lu girentuximab, STARLITE 1, Abs#TPS4610, ASCO 2024