- Presented at the 2022 annual Congress of the European Society for Medical Oncology (ESMO), results from three studies co-authored by VHIO’s Cristina Suarez report on novel immune-based strategies, either as monotherapy or in combination, for the treatment of kidney cancer.
- The phase III COSMIC-313 trial is the first study to evaluate triplet therapy in previously untreated advanced clear cell renal cell carcinoma. Data show that the addition of first line cabozantinib to nivolumab-ipilimumab significantly improves progression-free survival.
- First results of the phase II KEYNOTE-B61 study assessing the efficacy of combinatorial immunotherapy with pembrolizumab plus lenvatinib as first-line treatment for patients with advanced non-clear cell renal cell carcinoma show promising antitumor activity and a manageable safety profile.
- The phase III IMmotion010 investigators have however reported negative results. Atezolizumab as adjuvant monotherapy in patients with renal cell carcinoma and increased risk of disease recurrence after surgery, failed to improve outcomes in the intention to treat population.
Immunotherapy continues to step up in the treatment of an increasing number of tumor types, including kidney cancer. While rare, renal cell carcinoma (RCC) is the most common type of kidney cancer in adults accounting for more than 80% of cases, and non-clear renal cell carcinoma (nccRCC), encompassing a heterogeneous group of renal cell cancer subtypes, represents between 25-30% of these tumors.
Latest data from three clinical trials, co-authored by Cristina Suarez, a Clinical Investigator of VHIO’s Genitourinary, Central Nervous System (CNS) Tumors, Sarcoma and Cancer of Unknown Primary Site Group, were selected to showcase during this week’s annual Congress of the European Society for Medical Oncology (ESMO), 09 – 13 September, Paris, France. Results from COSMIC-313 (1), KEYNOTE-B61 (2), and IMmotion010 (3) report on the efficacy of novel immune-based strategies, either as monotherapy or in combination, in patients with ccRCC and nccRCC.
COSMIC-313: the first study to assess triplet immune-based therapy versus standard of care immunotherapy doublet in advanced renal cell carcinoma
Clear cell renal cell carcinoma is the most common subtype of RCC accounting for 75% of cases. Combinations of the monoclonal antibody cabozantinib plus immunotherapy nivolumab, and nivolumab combined with ipilimumab are both standards of care for the first-line treatment of these tumors.
“With progression-free survival as the primary endpoint, COSMIC-313 was designed to evaluate the efficacy of adding monoclonal antibody cabozantinib to immunotherapy with nivolumab and ipilimumab as a triplet treatment strategy versus placebo with nivolumab plus ipilimumab in this population,” says Cristina Suarez, a co-investigator and author of this present study.
Cabozantinib is an inhibitor of tyrosine kinases receptors including MET, VEGFR and TAM kinases, and promotes an immune-permissive environment which could enhance response to immune checkpoint inhibitors. The combination of PD-1 inhibitor nivolumab with ipilimumab, another antibody that binds to the CTLA-4 protein, boosts an immune response to tumor cells and triggers T cells to attack and destroy cancer cells.
This global, double-blind, randomized COSMIC-313 phase III study enrolled 855 previously untreated patients with clear cell advanced RCC, 428 of whom received the triplet experimental combination, and 427 who were treated with the immunotherapy doublet. Late-Breaking data (1) presented during a Presidential Session by lead author Toni K. Choueiri, Dana-Farber Cancer Institute, Boston (USA), show that the addition of cabozantinib significantly improved progression-free survival and reduced the risk of disease progression by 27%. The overall response rate in the prespecified intention-to-treat population was 43% with the triplet combination versus 36% with the standard immunotherapy doublet.
“We now await more mature data to see if these results translate in improved overall survival,” adds Cristina Suarez, a Medical Oncologist at the Vall d’Hebron University Hospital’s Medical Oncology Department (Vall d’Hebron Barcelona Hospital Campus), headed by VHIO’s Director Josep Tabernero.
KEYNOTE-B61: first results show promise of combinatorial therapy in patients with previously untreated advanced non-clear cell renal cell carcinoma
Non-clear cell renal cell carcinoma (nccRCC), accounting for around 25% of all RCC, is a heterogeneous group of kidney cancers, encompassing multiple histologies with different molecular features. Over recent years, there have been several advances in the treatment of advanced nccRCC, but due to the infrequency of these tumors, the improved management of these patients has been limited. Seeking out novel, more effective treatment approaches therefore represents an unmet clinical need.
Combined therapy with pembrolizumab, a PD-1 blocking immunotherapy that triggers T-cells to find and kill cancer cells, with targeted therapy lenvatinib, a multireceptor tyrosine kinase inhibitor, has previously shown improved response rates, progression-free survival, and overall survival compared with sunitinib as first line therapy in patients with ccRCC (4). In nccRCC, first-line pembrolizumab as monotherapy has shown promising antitumor activity in this patient population (5).
“Based on the promising results from these previous studies, the phase II single-arm KEYNOTE-B61 study was designed to evaluate pembrolizumab plus lenvatinib in patients with non-clear cell renal cell carcinoma,” says Cristina Suarez, a KEYNOTE-B61 investigator and co-author of this study.
Enrolling 147 patients with previously untreated advanced nccRCC, the primary endpoint of this study was confirmed overall response rate to this combinatorial therapy. Results of this current preliminary analysis (2), selected as an oral presentation and presented during a Proffered Paper session by lead author Laurence Albiges, Institut Gustave Roussy, Villejuif (France), show that at cutoff, in those 82 patients with 24 or more weeks’ follow-up, with a median of 8.2 months, the confirmed overall response rate was 47%. The six-month progression-free survival rate was 72% and the overall survival rate was almost 88% at six months.
“This novel combination shows promising antitumor activity and a manageable safety profile, with no new safety signals. Considering the high heterogeneity of these tumors, these results are encouraging, particularly given the different molecular alterations and their clinical and therapeutical implications,” observes Cristina Suarez.
IMmotion010: adjuvant immunotherapy fails to improve outcomes in patients with renal cell carcinoma at increased risk of recurrence after surgery
The standard of care for loco-regional RCC is nephrectomy, but many patients unfortunately experience disease recurrence. While the advent of immunotherapy has led to improved outcomes in the adjuvant setting across several tumor types, results have largely been disappointing in kidney cancer.
The phase III, multicenter, randomized, double-blinded IMmotion010 clinical trial assessed the efficacy and safety of the anti-PD-L1 monoclonal antibody atezolizumab versus placebo as adjuvant therapy in 778 patients with RCC at increased risk of relapse after surgery. “Positive data previously reported from the KEYNOTE-564 study of pembrolizumab (6), another monoclonal antibody with a similar mechanism of action, led us to explore atezolizumab in this setting and thus potentially expand the therapeutic arsenal for patients with RCC and increased risk of relapse post-surgery,” observes Cristina Suarez, a co-author of this study.
Late breaking data from IMmotio010, were also selected to first outing as an oral and were presented during a Proferred Paper session by co-first author Axel Bex, The Royal Free London NHS Foundation Trust (UK). The results, published in parallel in The Lancet (7), failed to show improved clinical outcomes versus placebo in the intend-to-treat population.
“As we collectively seek to improve outcomes for our patients, negative clinical trials also represent an important piece of the puzzle. Not only do they provide important insights into which new treatment strategies should not be used in a particular patient population, they also help to generate new hypotheses and directions in the management of cancer,” concludes Suarez.
References:
1. Toni K. Choueiri, Thomas Powles, Laurence Albiges, Mauricio Burotto, Cezary Szczylik, Bogdan Zurawski, Sergio Trevino, Eduardo Yañez, Umberto Basso, Alberto Suarez, Luis Enrique Fein, Fabio A. Schutz, Daniel C.Y. Heng, Fong Wang, Fabio Mataveli, Yu-Lin Chang, Maximiliano van Kooten, Cristina Suarez, Robert J. Motzer. Phase 3 study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced RCC (aRCC) of IMDC intermediate or poor risk (COSMIC-313).
ESMO Congress 2022 session details:
Presidential Symposium III
Date: Monday, 12th September
Time: 16:30 – 18:15h
LBA8 – Phase 3 study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313).
Speaker: Toni K. Choueiri (Boston, USA)
Lecture Time: 16:30 – 16:45h
2. Laurence Albiges, Howard Gurney, Vagif Atduev, Cristina Suarez, Miguel Climent, David Pook, Piotr Tomczak, Philippe Barthelemy, Jae Lyun Lee, Taron Nalbandian, Viktor Stus, Thomas Ferguson, Pawel Wiechno, Erhan Gokmen, Louis Lacombe, Craig Gedye, Rodolfo F. Perini, Manish Sharma, Chenxiang Li, Chung-Han Lee. Phase 2 KEYNOTE-B61 Study of Pembrolizumab (pembro) + Lenvatinib (lenva) as First-Line Treatment for Non-Clear Cell Renal Cell Carcinoma (nccRCC).
ESMO Congress 2022 session details:
Proffered Paper session 2: GU tumours, non-prostate
Date: Monday, 12th September
Time: 14:45 – 16:15h
1448O – Phase II KEYNOTE-B61 study of pembrolizumab (Pembro) + lenvatinib (Lenva) as first-line treatment for non-clear cell renal cell carcinoma (nccRCC).
Speaker: Laurence Albiges (Villejuif, Cedex, France)
Lecture Time: 15:40 – 15:50h
3. Axel Bex, Robert Uzzo, Jose Antonio Karam, Viraj A. Master, Frede Donskov, Cristina Suarez, Laurence Albiges, Brian Rini, Yoshihiko Tomita, Ariel Kann, Giuseppe Procopio, Francesco Massari, Matthew Zibelman, Igor Antonyan, Mahrukh Huseini, Debasmita Basu, Bo Ci, William Leung, Omara Khan, Sumanta Pal. IMmotion010: efficacy and safety from the Phase III study of atezolizumab (atezo) vs placebo (pbo) as adjuvant therapy in patients with renal cell carcinoma (RCC) at increased risk of recurrence after resection.
ESMO Congress 2022 session details:
Proffered Paper session 1: GU tumours, non-prostate
Date: Saturday 10th September.
Time: 10:15 – 11:45h.
LBA66 – IMmotion010: efficacy and safety from the Phase III study of atezolizumab (atezo) vs placebo (pbo) as adjuvant therapy in patients with renal cell carcinoma (RCC) at increased risk of recurrence after resection
Speaker: Axel Bex (London, United Kingdom)
Lecture Time: 10:15 – 10:25h
4. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300.
5. McDermott DF, Lee JL, Ziobro M, Suarez C, Langiewicz P, Matveev VB, Wiechno P, Gafanov RA, Tomczak P, Pouliot F, Donskov F, Alekseev BY, Shin SJ, Bjarnason GA, Castellano D, Silverman RK, Perini RF, Schloss C, Atkins MB. Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2021 Mar 20;39(9):1029-1039.
6. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021 Aug 19;385(8):683-694.
7. Adjuvant atezolizumab vs placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Sumanta Kumar Pal, MD, Robert Uzzo, MD, Jose Antonio Karam, MD, Viraj A. Master, MD, Frede Donskov, MD, Cristina Suarez, MD, Laurence Albiges, MD, Brian Rini, MD, Yoshihiko Tomita, MD, Ariel Galapo Kann, MD, Giuseppe Procopio, MD, Francesco Massari, MD, Matthew Zibelman, MD, Igor Antonyan, MD, Mahrukh Huseni, MS, Debasmita Basu, MS, Bo Ci, PhD, William Leung, PharmD, Omara Khan, MS, Sarita Dubey, MD, Axel Bex, MD.
