Toxicity management of Antibody-Drug Conjugates (ADCs) therapies

The SABC session on toxicity management of next-generation therapies largely focused on strategies to mitigate AEs associated with ADCs and newer HR+ treatments (e.g., oral SERDs, AKTis).

(#ED08-01; McArthur)

• Interstitial lung disease (ILD) was highlighted as a major cause for concern with T-DXd
  • Enhanced monitoring and toxicity management guidelines implemented in DESTINY-Breast03 resulted in no deaths due to ILD; however, frequency of monitoring may subsequently add on additional patient burden
  • Even with increased monitoring, DESTINY-Breast04 was noted to have 3 deaths due to ILD/pneumonitis underscoring the need for continued vigilance for this AE with the speaker highlighting detailed ILD management guidance for all eligible patients
  • In particular, she emphasized that if ILD is Gr2+, T-DXd must be permanently discontinued and that T-DXd should only be restarted following a confirmed and resolved (Gr0) case of Gr1 ILD/pneumonitis
• Other common AEs associated with T-DXd seen across multiple trials include nausea, fatigue, and alopecia though these were seen as more “familiar” AEs in this space
  • During the later discussion a patient advocate, who was enrolled in one of the DESTINY-breast trials spoke about T-DXd’s AEs and the “horrific” side effects and highlighted the negative impact they had on her QoL
• Trodelvy was noted to have a distinct toxicity profile compared to HER2-targeting ADCs with neutropenia, diarrhea and nausea being the most common AEs
  • Speaker emphasized that ILD is not associated with Trodelvy; however, rate of neutropenia (~50%) was stated to be a real-world management problem though both neutropenia and diarrhea were noted to be manageable with dose modification and/or concomitant medications and not typically leading to discontinuation
• Stomatitis and ocular events were mentioned as AEs of special interest for Dato-DXd
  • Prophylactic dexamethasone mouthwash (with or without cryotherapy) was recommended to manage stomatitis
  • Close ophthalmologic monitoring was also noted to be critical with Dato-DXd
• Toxicities related to the combination of TROP2-ADCs and IO was noted to need further discussion given that there are on-going studies looking to move these regimens into the curative intent setting (ie.TROPION-Breast03, TROPION-Breast04, ASCENT-05),
• It was noted that the toxicity profile of ADCs can potentially be optimized through dose-optimization strategies, drug engineering, pharmacogenetics, and utilization of diagnostic tools
  • Example of a mitigation strategies were the use of wearable devices to continuously monitor vital signs during treatment of ILD-causing regimens (i.e. T-DXd) and UGT1A1 testing to adapt the starting dose of Trodelvy
• While efficacy drives treatment choice for physicians, Trodelvy has an opportunity to differentiate against key in-class competitors with its distinct safety profile.
  • • In particular, the AEs that appear to be specific to both T-DXd and Dato-DXd appear to have significant impact on patient quality of life even at Gr2, potentially weakening AZ’s narrative around improved QoL for patients treated with T-DXd or Dato-DXd

Next generation therapeutics in hormone positive breast cancer: balancing efficacy and tolerability

(#ED08-02; Mayer)

• The efficacy and safety of agents for HR+ disease in both advanced and early-stage settings were introduced including CDK4/6i, PIK3CAi, AKTi and oral SERDs
  • The speaker highlighted that each CDK4/6i has differencing toxicity profiles and safety monitoring needs
  • Oral SERDS were thought of as well tolerated drugs with the most common side effects being GI toxicities (nausea, vomiting, diarrhea) and less common side effects being bradycardia and visual disturbances
  • mTOR/PI3K/AKT pathway inhibitors were also outlined including everolimus (BOLERO-2), alpelisib (SOLAR-1) and capivasertib (CAPItello-291)
    • Diarrhea, rash, and hyperglycemia were stated to be the most frequent AEs associated with capivasertib; it was emphasized that prophylaxis needs for capivasertib is still yet to be determined
  • Similar to the ADC discussions, the speaker highlighted the need to consider an appropriate balance of efficacy and tolerability to maximize therapeutic index and help patients continue effective treatment

Pannel Discussion

(McArthur, Mayer, Johnson)

• Various dose modification strategies were discussed with a focus on the importance of communication with individual patients to help continue with treatment
• A regulator from the audience highlighted FDA’s Project Optimus, an initiative to reform current dose optimization and dose selection paradigm that encourages sponsors to investigate a wider range of dosages in earlier phases of trials
  • In general, the panelists and KOLs from the audiences agreed that there should be movement away from the MTD and towards MED