Advertisement


Ann H. Partridge, MD, MPH, and Véronique Diéras, MD, on the Future of Cytotoxic Therapy: Antibody-Drug Conjugates?

2022 ASCO Annual Meeting

Advertisement

Ann H. Partridge, MD, MPH, of Dana-Farber Cancer Institute, and Véronique Diéras, MD, of the Centre Eugène Marquis, discuss the many challenges posed by next-generation antibody-drug conjugates (ADCs). They include side effects such as hematotoxicity, gastrointestinal toxicities, and interstitial lung disease; tumor targeting and payload release; drug resistance; and the urgent need to understand ADCs’ mechanisms of action to better sequence and combine drugs.



Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.
Ann H. Partridge: Veronique, it's been a pretty exciting ASCO to be a breast cancer doctor and researcher. Tell me about these new drugs, the antibody conjugates that are making such a splash. Véronique Diéras: Yes. And in fact, it took more than a century to have this targeted chemotherapy in order to improve the therapeutic index of cytotoxic chemotherapy. We were using TDM-1 for many years, but the third generation of ADC have some particular and mainly the bystander effect what we call. So there is a release of the cytotoxic, the payload of the antibody in the micro environment, leading to activity in tumor cells that might not express the target of the ADC. So the bystander effect may increase the efficacy of the ADC, but also perhaps the toxicity. Ann H. Partridge: So it allows for that tumor heterogeneity that we're learning so much about to be targeted? Véronique Diéras: Yes, exactly. Tumor heterogeneity and moreover targeting tumor cells with low expression. We know, for instance, with the anti-ER therapy, it was active only in case of early to free expression, like for TDM-1 trastuzumab. And then with this new ADC and the bystander effect, there may be some activity on HE. Ann H. Partridge: R2 low expression, breast cancer. Ann H. Partridge: Yeah, and what do you mean by activity? What have we seen both in your work and what we saw here at ASCA? Véronique Diéras: Trastuzumab deruxtecan was very active in HER positive breast, metastatic breast cancer, according to the [inaudible] breast of free. But at this ASCO, we heard about the activity in HER2 low breast cancer. We have already refuted data from the early clinical trials, but we have the release of destiny breast or four comparing Trastuzumab deruxtecan versus chemotherapy choice of the physician. In every treated patient mainly ER positive too low, but some were negative. And clearly the results were impressive with a superiority, not only in probation free survival, but in response rate and interval survival. That means a lot for our patient because I think there will be a major impact for two mobile in our clinical practice. Ann H. Partridge: Right. And it worked in all subsets. Right? Véronique Diéras: Exactly. Ann H. Partridge: All subtypes. Yeah. If they express some HER2, right? Véronique Diéras: Yes. HER2 low, even if it's ER negative. So what we may call triple negative by the definition of today, we may have some activity too. Ann H. Partridge: That's right. About 30% express some HER2 correct? Véronique Diéras: Yes. Ann H. Partridge: Something like that. And what about the tolerability of these drugs? What are we learning? Véronique Diéras: There's no new safety signals from what we know from destiny breast free, it was an update of the safety during this meeting too. But perhaps we have to be cautious about interstitial lung disease, ILD, but in fact the incidence on the severity of ILD decrease with the implementation of guidelines and perhaps more over treating less pretreated population. Ann H. Partridge: So now we have a number of monoclonal antibody, conjugate drugs, where do we go from here? Where do we need to go research wise and what can we do on Monday in the clinic? Véronique Diéras: So on Monday in the clinic, we may use precision risk account, but in fact, we have many ADC with different target from HER2 low from HER3 and from [inaudible]. Véronique Diéras: And we have activity, I think HER3, we have as a preliminary development, but it's very exciting data. We have from the phase one and two study, but for tomorrow, what we need to know the best, we will address this ADC on the sequencing, the choice of the ADC for each patient. So today we say, considering the result we have with Trastuzumab [inaudible] HER2 low, ER positive, I will say the best choice will be Trastuzumab deruxtecan because we have an impact on world survival, but we may have activity with Trop2 ADC. So we have for the next future to evaluate the sequencing of this ADC, to evaluate the mechanism of resistance, because it'll have an important value to set the sequence. And also perhaps combination because we know from cyto toxic chemotherapy. When we combine with other drug immune checkpoint inhibitor, PAP inhibitor, sometimes we may have increase of activity. So we have a lot. I think it's the beginning of the story of it, in fact. Ann H. Partridge: So the beginning, and wouldn't it be nice if we could have a cocktail and then move it into the earlier stage setting and effect more cures? Véronique Diéras: Yes. Ann H. Partridge: That's what we want to see ultimately. Véronique Diéras: Yes, exactly. I was thinking of that, looking to the result of this of study of four. When I see the response rate in every pre-treated population. What may be the impact for instance, in the new adjuvant setting for ER positive, HER2 low, because we know usually the PCR is very low in ER positive diseases. So perhaps we have to evaluate Trastuzumab in the adjuvant setting to increase the PCR to have an impact on the cure of the patient. Ann H. Partridge: All right. I heard it here. I think that's the future. Thank you so much Veronique for joining me. Véronique Diéras: Thank you.

Related Videos

Neuroendocrine Tumors

Mairéad G. McNamara, PhD, MBBCh, on Neuroendocrine Carcinoma: Findings on Liposomal Irinotecan Plus Fluorouracil and Folinic Acid or Docetaxel

Mairéad G. McNamara, PhD, MBBCh, of The Christie NHS Foundation Trust, discusses phase II findings of the NET-02 trial, which explored an unmet need in the second-line treatment of patients with progressive, poorly differentiated extrapulmonary neuroendocrine carcinoma. In the trial, the combination of liposomal irinotecan, fluorouracil, and folinic acid, but not docetaxel, met the primary endpoint of 6-month progression-free survival rate (Abstract 4005).

Multiple Myeloma

Paul G. Richardson, MD, on Multiple Myeloma: New Data on Lenalidomide, Bortezomib, and Dexamethasone, With or Without ASCT

Paul G. Richardson, MD, of Dana-Farber Cancer Institute, discusses phase III findings from the DETERMINATION trial, which showed that, for patients with newly diagnosed multiple myeloma, lenalidomide, bortezomib, and dexamethasone (RVd) with or without autologous stem cell transplant (ASCT) and lenalidomide maintenance to disease progression resulted in the longest median progression-free survival reported for each approach, and a highly significant difference in progression-free survival in favor of early transplant. While overall response rates were similar, rates of MRD favored early transplant also, but toxicity was greater and quality of life was transiently but significantly diminished. No overall survival advantage has been observed to date (Abstract LBA4).

Breast Cancer

Tara B. Sanft, MD, on How Diet and Exercise May Affect Completion of Chemotherapy for Breast Cancer

Tara B. Sanft, MD, of Yale University, discusses the results of the LEANer study (Lifestyle, Exercise, and Nutrition Early After Diagnosis) in women with breast cancer. It showed that patients with newly diagnosed disease who were just starting chemotherapy could improve physical activity and diet quality. While both groups had high rates of treatment completion, women in the intervention who exercised at or above the recommended levels did better in terms of treatment completion, with fewer dose reductions and delays (Abstract 12007).

 

Skin Cancer

Georgina V. Long, MD, PhD, on Melanoma: New Data on Pembrolizumab, Dabrafenib, and Trametinib

Georgina V. Long, MD, PhD, of the Melanoma Institute Australia, The University of Sydney, discusses findings from the NeoTrio trial on neoadjuvant pembrolizumab alone, in sequence with, or concurrent with dabrafenib plus trametinib in patients with resectable BRAF-mutant stage III melanoma. The study may help clinicians determine the optimal combination of therapy (Abstract 9503).

Head and Neck Cancer
Supportive Care

Carryn M. Anderson, MD, on Head and Neck Cancer: New Data on Avasopasem Manganese for Oral Mucositis

Carryn M. Anderson, MD, of the University of Iowa Hospital, discusses phase III results of the ROMAN trial of avasopasem manganese for patients with severe oral mucositis who are receiving chemoradiotherapy for locally advanced, nonmetastatic head and neck cancer. Compared with placebo, avasopasem manganese improved severe oral mucositis (Abstract 6005).

Advertisement

Advertisement




Advertisement