19 oktober 2020: Btron: ESMO 2020

Wanneer het anti-PD medicijn nivolumab en cabozantinib worden gecombineerd als eerstelijnsbehandeling bij uitgezaaide nierkanker en vergeleken met de standaardbehandeling sunitinib dan geeft deze combinatiebehandeling veel betere resultaten wat betreft progressievrije overleving, algehele overleving en responspercentage. De onderzoekers spreken over superieure verbeteringen. Het risico op ziekteprogressie of overlijden werd met bijna 50% verminderd, overlijden met 40% en het responspercentage verdubbelde.  

Er was een consistent voordeel van de combinatiebehandeling ten opzichte van sunitinib in tal van subgroepen, waaronder leeftijd, geslacht, PD-L1-expressie, botmetastasen, risicogroep van het International Metastatic RCC Database Consortium (IMDC) en regio van de wereld.

Hoewel meer dan 50% van de patiënten in de combinatie-arm een dosisverlaging van cabozantinib nodig had vanwege bijwerkingen moest slechts 3% beide geneesmiddelen stoppen vanwege toxiciteit vergeleken met 9% van de patiënten in de sunitinibgroep. Het totale aantal ernstige bijwerkingen was vergelijkbaar tussen de groepen, maar levertoxiciteit kwam vaker voor in de combinatiegroep. Wat immuungerelateerde bijwerkingen betreft, had 19% van de patiënten in de combinatiegroep corticosteroïden nodig; maar slechts 4% had 30 dagen of langer corticosteroïden nodig.

Studyleider Dr Toni K. Choueiri, Director, The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and The Jerome and Nancy Kohlberg Chair and Professor of Medicine, Harvard Medical School, Boston, US zegt: "De resultaten met combinatietherapie waren statistisch significant en klinisch betekenisvol. Het risico op progressie of overlijden werd met bijna 50% verminderd, overlijden met 40% en het responspercentage verdubbelde. Dit wordt een belangrijke behandelingsoptie om uit te kiezen." 

De studie resultaten:

Study results
The study enrolled a total of 651 patients (22.6% favorable risk, 57.6% intermediate risk, 19.7% poor risk; 24.9% PD-L1 ≥1%). Participating patients were randomized to nivolumab + cabozantinib (n = 323) or sunitinib (n = 328).

With 18.1 months median (10.6 month minimum) study follow-up, all 3 efficacy endpoints were met.

The investigators observed that nivolumab + cabozantinib significantly improved PFS (HR 0.51 [95% CI 0.41–0.64], P < 0.0001; median, 16.6 v 8.3 mo) and OS (HR 0.60 [98.89% CI 0.40–0.89]; P = 0.0010; medians not reached) versus sunitinib. These results were consistent across prespecified IMDC risk and PD-L1 subgroups.

The objective response rate (95% CI) was significantly higher with nivolumab in combination with cabozantinib compared to sunitinib (55.7% [50.1–61.2] v 27.1% [22.4–32.3]; P < 0.0001), and 8.0% v 4.6% of patients achieved complete response. Median duration of response was 20.2 months for patients treated with nivolumab + cabozantinib compared to 11.5 months for patients treated with sunitinib.

Adverse events
In the study, more than 50% of patients in the combination arm needed a dose reduction of cabozantinib due to adverse events. But only 3% had to stop both drugs because of toxicity compared to 9% of patients in the sunitinib arm.

Any-grade treatment-related adverse events (TRAEs) occurred in 96.6% v 93.1% of patients treated with nivolumab + cabozantinib v sunitinib . One treatment-related death occurred with nivolumab + cabozantinib and 2 patients died with sunitinib.

The overall rate of serious treatment-related adverse events was similar between arms (60.6% v 50.9% grade ≥3), but liver toxicity was more common in the combination arm. As for immune-related side-effects, 19% of patients in the experimental arm needed corticosteroids with just 4% of participating patients needing corticosteroids for 30 days or longer.

Treatment-related adverse events led to discontinuation in 8.8% of the participating patients treated with sunitinibnivolumab or cabozantinib in 15.3%, nivolumab with cabozantinib in 3.1%, nivolumab only in 5.6%, and C only in 6.6% of patients.

Advantages of combination therapies
These findings add to mounting evidence showing the advantages of combination therapy over single drugs. Similar to the CheckMate 9ER trial, the KEYNOTE-426 and JAVELIN Renal 101 trials [2][3] combined an immune checkpoint inhibitor with an anti-angiogenic drug, whereas CheckMate 214 combined two immune checkpoint inhibitors. [4]

“The results with combination therapy were statistically significant and clinically meaningful. The risk of progression or death was cut by almost 50%, death was cut by 40%, and the response rate doubled,” noted study author Toni K. Choueiri, M.D., the of Director of The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and The Jerome and Nancy Kohlberg Chair and Professor of Medicine, Harvard Medical School, Boston.

“This will become an important treatment option to choose from. The various combination treatments will unlikely be compared head-to-head, but I think the (health-related) Quality of Life (hrQoL) could differentiate this new therapy, as there was a statistical significance favoring the combination arm with both questionnaires we used. Another factor to consider is that clinicians are familiar with both of these drugs.” [5]

“CheckMate 9ER met its efficacy endpoints and the combination can be considered a new first-line treatment option,” said Dominik Berthold, M.D., Head, Specialised Consultation for Urological Cancers Medical Oncology Service, Department of Oncology, Lausanne University Hospital, Switzerland, commenting on the findings of the study.

Het studierapport werd gepresenteerd op ESMO 2020 naar aanleiding van vier studies:

Clinical trials
A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 9ER) – NCT03141177
Cabozantinib S-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors – NCT02496208
Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426) – NCT02853331
A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101) – NCT02684006
Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214) – NCT02231749


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