EIKCS 2022: The Pieter de Mulder Award Lecture

(UroToday.com) During the first session of the third day of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting, Dr. Tom Powles presented Dr. Albiges with the Pieter de Mulder Award in Oncology. In introducing her, Dr. Powles emphasized that Dr. Albiges has provided important scientific insights into the underlying biology and treatment of renal cell carcinoma, has provided critical involvement in shaping the guidelines for the treatment of this condition, and has influenced colleagues and trainees in this field.

Following Dr. Powles introduction, Dr. Albiges presented the Pieter de Mulder Lecture in Oncology, focusing on her learning from renal cell carcinoma (RCC), intermixing her own clinical, personal and professional experiences with the observations of her own research between medical school and the present day.

To provide context for this, she first explained how she got to studying and treating RCC, beginning with medical school in Paris in the late 1990s and early 2000s. As her first resident rotation, she discovered her interest in the Cancer Center and the care of patients with cancer, though her initial interest was in breast cancer. Nearly halfway through her residency, during a Radiology rotation, Dr. Albiges was drawn to a case of mTOR induced pneumonitis which prompted her to dive into this further. Being based as the Gustav Rousey, she “knocked at the door of a Giant”, approaching Bernard Escudier. While she subsequently completed a Master’s degree in Biology focussing on breast cancer, she was increasing interested in renal cell carcinoma biology and the chart review work she had undertook. Therefore, she undertook another research project in RCC, under the guidance of Dr. Escudier and this time focusing on those patients who had evidence of complete remission with the use of tyrosine kinase inhibitors. This work, based on a multi-center cohort in France was published in the Journal of Clinical Oncology. She described as critical in developing perspective on RCC a reviewer’s comment on this work which sought to understand the denominator of the number of patients treated to identify these complete responders. Going back to the centers that contributed the data, she found that overall, the 67 patients with complete remission represented only 0.7% of those treated with tyrosine kinase inhibitors. This work crystalized her interest in pursuing kidney cancer.

Moving forward, she spent the last six month rotation of her residency in pathology. It was during this time that she became interested and engaged with the non-clear cell histology space. As a result, she dedicated her Doctoral research to the characterization of papillary RCC. 

This work demonstrated the importance of MET as a potential target for patients with papillary renal cell carcinoma. Then, in a trial that “nearly no one knows”, Dr. Albiges and colleagues performed the first prospective molecular trial using crizotinib in metastatic type I papillary RCC.

Finishing her training, Dr. Albiges then moved to Boston to work with Dr. Toni Choueiri, at the Lank Center for Genitourinary (GU) Oncology at the Dana-Farber Cancer Institute. In doing so, Dr. Albiges references this as moving “from one Giant to Another One”. During her time in Boston, Dr. Albiges subsequently worked on papillary RCC using data from The Cancer Genome Atlas which, through its molecular characterization again identified MET as a potential target. This led to the phase II trial of savolitinib among patients with papillary RCC with MET driven tumors, with biomarker selection as defined based on evidence of a MET mutation, MET amplification, a ligand mutation (HGF) or chromosome 7 copy number alteration.

During her 18 months working at the Dana-Farber Cancer Institute, Dr. Albiges conveys discovering that “anything related to RCC was of interest to me”. This included a large collaborative effort to characterize the effect and mechanisms of obesity on renal cell carcinoma outcomes. However, in May 2015, obligations brought her back to France to work at Gustav Rousey. Upon her return, she continued international collaborations including with Danny Heng (France, Canada, and Korea) involving the molecular screening of papillary RCC tumors to better understand MET as a prognostic factor in the disease process.

This work, together, contributed to the design of the SAVOIR study, the first randomized phase III trial performed in a molecularly defined population. Published in 2020, this work suggested the benefit of savolinitinb as a MET inhibitor over sunitinib. She emphasized that, beyond these clinical data, performing this trial emphasized that it is difficult to perform a trial with molecular pre-screening in patients with rare and aggressive tumors because both the treating physicians and patients want to move quickly to initiate treatment.

This work, along with other experiences rising in seniority within her department, led her to a position to shape (and change) guidelines for the management of patients with papillary RCC. As her clinical practice grew, she noted that there were many young female patients with papillary RCC, an observation which again prompted research endeavours. Along with mentees, she undertook work to understand the response of fumarate hydratase (FH)-mutated papillary RCC to systemic therapy. They found, notably using real world data from France, that single agent immunotherapy was not effective as a later line therapy for patients with papillary disease, with objective response rates of approximately 10% and progressive free survival of only 3 months.

In November 2015, she was asked to take over the genitourinary oncology group at Gustav Rousey. Around the same time, nivolumab became standard of care as second line therapy in RCC. However, as an accruing site to the CheckMate-025 trial, they noted that many patients didn’t appear to benefit. Thus, she and other sought to assess whether response to single agent nivolumab would be the same in real world practice as within the trial, launching the GETUG AFU 26 NIVOREN study as a result. They further wondered if this large scale, phase IV study could support the development of a large translational research program, which formed the basis of the NIVOREN translational arm. Now presented and published many times over, the NIVOREN trial pragmatically enrolled patients with metastatic RCC with a clear cell component who had failed at least one line of VEGF/VEGFR inhibition to this prospective single arm, multicenter study of single agent nivolumab. Following the enrollment of the first patient in January 2016, accrual was so rapid and successful that the trial was expanded from the initially planned sample size of 300 to 720 patients. Between January 2016 and July 2017, these 720 patients were treated across 25 centers in France. This allowed a wide clinical experience with the use of this agent in the country, even before it was approved for reimbursement.

In some of their first analyses of the NIVOREN trial, Dr. Albiges and colleagues compared the results to the CheckMate-025 trial finding, over a longer follow-up (24 vs 14 months) that median progression free survival was somewhat lower (3.7 vs 4.6 months) but that median overall survival was comparable (24.5 vs 25.0 months). This study has subsequently proven to be a platform to address numerous clinically meaningful questions, including effects on specific metastatic sites (including the first report of the effect of nivolumab on brain metastasis), specific patient populations, and the effect of concurrent medication use (including corticosteroids, statins, antibiotics, and proton pump inhibitors). Additionally, this work provided insight that there is limited primary tumor response in this heavily pre-treated population.

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In addition to these clinical analyses, the NIVOREN translational program as provided a platform for the assessment of many clinically relevant questions, along with providing the impetus for collaborations with many outside laboratories, including pathologists.

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In doing so, they have assessed the effect of PD-1, AXL, and PBRM-1 expression with outcomes following nivolumab therapy, sought to identify approaches for fresh blood immune cell monitoring during treatment, and performed molecular classification of RCC tumors. Additionally, this work, in collaboration with Dr. Friedman’s lab, allowed the discovery and validation of Teffector and angiogenesis signatures as well as an immune classification of ccRCC.

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She highlighted that the NIVOREN trial has demonstrated that a trial may be quickly set up when pharm and academic interests are aligned. In doing so, we can see early adoption of a new treatment paradigm while also providing a platform for investigation and building careers for young academics. She further emphasized that this work has highlighted the importance of a geographically diverse network and collaborative efforts. To this end, she highlighted the importance of having “as many people and as much talent working on the project as possible”. In building her career, she stressed how important collaborations have been. To this end, she emphasized that “most of what I’ve learned, I’ve learned from others”. Additionally, she particularly noted the value of having women in leadership positions as mentors and role models. In doing the work described above and building the network necessary to do so, Dr. Albiges noted her evolution from mentee to mentor.

While highlighting the great amount of work that has been achieved, she further noted the many questions left to answer in RCC.

Presented by: Laurence Albiges, MD, PhD, medical oncologist, Institut Gustave Roussy