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ASCO 2024

ASCO 2024: In It for the Long Run: Updated Outcomes From Phase III Trials

(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL was host to the Oral Abstract Session: Genitourinary Cancer-Kidney and Bladder. Dr. Camillo Porta discussed the Updated Outcomes from Phase III Trials in Bladder and Kidney Cancer.

Dr. Porta discussed the updated outcomes of three trials presented at the ASCO 2024 meeting following presentations from Drs. Charlene Mantia, Robert J. Motzer, and Matthew D. Galsky.

  • Abs. #4507 – Partitioned overall survival (OS) over 4 years in CheckMate 9ER
  • Abs. #4508 –The final OS analysis from the JAVELIN Renal 101
  • Abs. #4509 – Characterization of complete responders from the CheckMate 901 trial

He began discussing the partitioned OS analysis from the CheckMate 9ER. To contextualize, Checkmate 9ER was a phase 3, randomized, open-label trial, that assigned patients with previously untreated clear-cell, advanced renal-cell carcinoma (aRCC) to receive either nivolumab plus cabozantinib or sunitinib. This study met its primary endopoint of progression-free survival and showed that the combination of nivolumab+cabozantinib doubled the median progression-free survival (16.6 vs 8.3 months) with sunitinib alone.1 The aim of this analysis was to evaluate treatment-free survival (TFS) based on the longer PFS and OS achieved with nivolumab+cabozantinib.1

In a recent survey from the Kidney Cancer Research Alliance (KCCure), aiming to understand how patients prioritize treatment selection and define treatment success, the possibility of discontinuing therapy, especially without significant toxicity, is a highly ranked outcome (see Figure below).2

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The partitioned OS analysis identified five different survival states during the first four years of the CheckMate 9ER study. The investigators noted a modest advantage in treatment-free survival (TFS) for the IO+TKI combination compared to TKI monotherapy (6.9 months vs. 4.6 months, respectively). However, the TFS without toxicity was only 3 months, with patients receiving the IO+TKI combination compared to 2.3 months for those treated with sunitinib, which means only 0.7 months overall without toxicity. It's important to note that these findings are based on clinical trial data and may not fully reflect real-world outcomes, which are often more favorable. The figure below illustrates the median TFS among different survival states.

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So how does this data compare to other available evidence? Dr. Porta presented a patient-level data analysis of patients from the CheckMate 214 study. This analysis showed that TFS was superior for the IO combination group vs. the Sunitinib group. The Overall TFS was 6.9 vs 3.1 months (intermediate/poor risk patients) and in the intention to treat population, the overall TFS was 7.8 vs 3.3 months. However, the TFS with TRAEs ≥ Grade 2 was 3.0 vs 1.6 months in the IO combo vs. TKI alone, respectively and the TFS without TRAEs ≥ Grade 2 was 3.9 vs 1.5 months.3 Similarly, in a partitioned OS analysis of the HCRN GU16-260 study-Cohort A, which is a phase II study of patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years followed by Salvage nivolumab/ipilimumab for up to 1 year. This partitioned analysis confirmed that TFS is longer with IO as compared to IO-TKI combinations, and that TFS was greatest in patients with favorable-risk disease.4 He went on to discuss a pooled analysis of 2,367 patients included in the Keynote-426, Javelin RENAL 101, and CheckMate 9ER studies. This study showed that TFS was modest and similar in the IO-TKI group vs the Sunitinib group (2.7 vs 2.9 months) and the TFS with toxicity was1.0 vs 0.6 months, and TFS without toxicity was 1.7 vs 2.3 months, respectively.5

image-2.jpg

To close his discussion on the partitioned OS analysis of the CheckMate 9ER study, Dr. Porta provided these key takeaways:

  • Partitioned OS analysis has been primarily utilized by regulatory authorities in cost-effectiveness analyses of oncological treatments.
  • It's imperative to incorporate this type of analysis into oncological clinical trials, ensuring that the results are thoroughly discussed with patients. (Time off treatment stands out as one of the most impactful outcomes for patients with aRCC.)
  • Despite the emergence of TFS as an essential patient-centered outcome in oncological clinical trials, it is unlikely that this endpoint would significantly influence the clinical decision-making process.
  • Despite the differences in TFS, he wouldn’t choose Ipilimumab/Nivolumab over Nivolumab/Cabozantinib as the first-line treatment for aRCC.

The final OS analysis from JAVELIN Renal 101 took center stage as the second item on the agenda. This phase 3 trial focused on previously untreated patients with aRCC (any IMDC risk score), comparing avelumab plus axitinib with the standard-of-care at the time, sunitinib. The updated analysis presented the trial's results, including the final OS analysis at a median follow-up of ≥68 months. While OS analyses favored Avelumab + Axitinib over Sunitinib, the difference did not reach statistical significance (median OS 44.8 vs. 38.9 months, p=0.067). However, PFS was notably longer with Avelumab + Axitinib compared to Sunitinib (median PFS 13.9 vs. 8.5 months, p<0.0001).6

Dr. Porta chose to employ GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) as a framework for grading the quality of evidence, applying it to JAVELIN Renal 101. He highlighted several factors: for the OS analysis in the overall population, this study's risk of detection bias was not serious (single study, adequate comparator of therapy at the time of study design, BICR assessment, and use of RECIST version 1.1). However, it had a serious risk of detection/performance bias due to the open-label design, and the certainty was only moderate according to GRADE. Furthermore, for the PFS analysis, the risk of detection bias was not serious, and certainty was high. However, for TRAEs, the risk of detection bias and the risk of imprecision were serious, resulting in low certainty according to GRADE. Further details of his analysis are provided in the accompanying figure.

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Dr. Porta then posed a question to the audience: Would you opt for a treatment in the first line setting for aRCC that doesn't improve OS, especially when you have four alternatives that do? He briefly discussed the results of the CheckMate 214 (7), KeyNote 426 (8), CheckMate 9ER,1 and CLEAR9 trials. All these trials, using different IO + TKI combinations or IO+IO combination,7 demonstrated improved OS when compared to sunitinib1,7,8 or everolimus9 alone in the treatment aRCC. The European Society of Medical Oncology (ESMO) guidelines for aRCC are outlined below, highlighting recommended treatment options that have all demonstrated improvements in OS. In contrast, JAVELIN Renal 101, currently not endorsed by these guidelines for aRCC treatment, stands apart. Therefore, Dr. Porta concluded that he would continue to adhere to the ESMO guidelines, the algorithm for first-line treatment of aRCC according to ESMO is shown below.

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The final item on the agenda was the study presented earlier by Dr. Galsky, which aimed to characterize complete responders and patients with lymph node-only metastasis from the CheckMate 901 trial. Dr Porta briefly discussed the CheckMate 901 study, this was a phase 3, multinational, open-label trial, that randomly assigned patients with previously untreated, unresectable or metastatic urothelial carcinoma to nivolumab plus gemcitabine-cisplatin for up to six cycles, followed by nivolumab maintenance for a maximum of 2 years, or to receive gemcitabine-cisplatin (GC) alone.10

In the CheckMate 901 study, 102 patients (16.8%) achieved a complete response (CR), 66 (10.8%) from the Nivolumab + GC group, and 36 (5.9%) from the GC alone group. Since lymph node-only patients enriched the whole CR group, further analyses were conducted on these patients. In patients with lymph-node only disease, Nivolumab + GC yielded higher overall response rates (+17.2%) and CR (+29.1%) rates, as well as significantly longer OS (+21.4 months) and PFS (+21.7 months), as compared with GC patients. However, CR were less likely to occur in patients with distant lymph nodes.

Dr. Porta further elaborated that lymph node-only metastatic disease in advanced urothelial carcinoma typically associates with favorable prognosis. These patients often experience prolonged disease-free survival and overall response rates with standard chemotherapy, with or without surgical consolidation.11 Therefore, it comes as no surprise that in the CheckMate 901 trial, patients with lymph node metastases only exhibited more complete responses, as well as longer OS and PFS when treated with Nivolumab + GC.

However, Dr. Porta noted that despite the promising results of the CheckMate 901 trial in the first-line setting of locally advanced/unresectable or advanced urothelial carcinoma, these findings were somewhat overshadowed by those of the EV-302 trial.12 This trial compared the combination of enfortumab vedotin + pembrolizumab (EV + P) versus platinum-based chemotherapy in previously untreated patients with locally advanced/metastatic urothelial carcinoma, demonstrating unprecedented benefits in overall survival and overall response rates. In the graphic below, the OS of both the CheckMate 901 trial and the EV-302 trial is depicted. Importantly, the median OS for the treatment arm in both studies was 21.7 months vs. 31.5 months in CheckMate 901 and EV-302, respectively. Therefore, the question arises as to whether this lymph node-only subanalysis of the CheckMate 901 trial is sufficient to counterbalance the significant impact of the EV-302 study.

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Dr. Porta highlighted that the combination of enfortumab vedotin + pembrolizumab (EV + P) also demonstrated remarkable efficacy in patients with lymph node-only disease. The objective response rate (ORR) was 77.5% in the EV + P arm compared to 53.4% in the control arm, and notably, the median overall survival (OS) was not reached in this subgroup. The ORR and complete response rate in the CheckMate 901 were 81.5% and 63.0% for Nivolumab+GC, respectively.

image-6.jpg

Moreover, identifying lymph node metastases can be challenging, as is assessing their response to treatment. The sensitivity of CT and MRI in detecting lymph node metastasis ranges between 40-50%. In this trial, CT was the imaging of choice suggested by the study protocol.

image-7.jpg

Bringing his presentation to a close, Dr. Porta highlighted his takeaways for the critical appraisal of the CheckMate 901 trial subanalysis of complete responders/LN+ only:

  • Lymph node-only disease is a favorable prognostic factor in advanced urothelial carcinoma patients. This is a disease setting where cure may potentially occur
  • To date, we do not have a standard of care for these patients
  • The combination of Nivolumab and GC appears to be effective in patients with lymph node-only advanced urothelial carcinoma. Additionally, with its fixed chemotherapy cycles and two-year immunotherapy duration, it offers a more patient-friendly approach compared to EV+P.
  • Nivolumab + GC should be considered as a potential standard treatment for patients with lymph node-only advanced urothelial carcinoma, particularly those with pelvic lymph node involvement, where downstaging is critical for proceeding with surgical consolidation.
  • Standardizing imaging protocols for lymph node-only disease is imperative for future trials in advanced urothelial carcinoma.

Presented by: Camillo Porta, MD, Full Professor of Medical Oncology at the A. Moro University of Bari in Italy

Written by: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024. 

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