ASCO GU 2019: Questions and Lessons Moving Forward from CARMENA: Which Treatment First? Medical Oncologist’s Perspective

San Francisco, CA ( Dr. Harshman gave the Medical Oncologist perspective of cytoreductive nephrectomy (CN) . As has been the case for many of these debates recently, there wasn’t much of a debate – both medical oncologists and urologists have been on the same page!

She starts by addressing the problem – for patients with distant renal cell carcinoma (RCC) metastatic renal cell carcinoma (mRCC), 5-year survival rates are still abysmal. Using SEER data, 5-year DSS rates for patients with mRCC are 11%. This is despite the rapid advances in systemic therapies that have become available for this disease space.

She then briefly reviewed the CARMENA study and its findings
Her main points:
  1. Systemic therapy alone is not inferior to CN + systemic therapy
  2. Patients were primarily poor-risk – which isn’t necessarily the population treated in a real-world setting
  3. In subgroup analysis, looking at intermediate risk patients, statistically speaking, you could not say that systemic therapy alone was non-inferior to CN+systemic therapy. However, the survival numbers actually suggested benefit with systemic therapy alone.
  4. The study did not address the question of low vs. high volume disease (metastatic burden) as most patients accrued on the trial had high volume metastatic burden
She then briefly touched upon the SURTIME study (Bex et al. ESMO 2017), which addressed sequencing rather than removing CN from the paradigm. This study had very poor accrual and was stopped early. However, some take-home points from the data that was obtained:
  1. A significant proportion of patients progress quickly – and a CN would mean a lost window to get systemic therapy into the patient
  2. Overall survival appeared to improve with deferred CN
Between the two studies, the general consensus at this time appears to support systemic therapy up front for patients that need systemic therapy. CN upfront should be reserved for patients that perhaps won’t need systemic therapy (low-volume metastases, the primary tumor is the majority of the tumor burden, good risk patients). This is supported by work from Brian Rini (Lancet 2016) that showed that some patients with mRCC do well on surveillance for months to years before requiring systemic therapy.

Hence, the future of CN in mRCC after CARMENA is …. Not so different than it was before CARMENA. Most practicing urologic oncologists and medical oncologists have not changed their practice significantly based on the results. Systemic disease needs systemic therapy still.

There are certain situations for which CN should still be considered though, and these are highlighted in the diagram below:

UroToday_ASCOGU2019_Harshman, MD _1.png

As mentioned by Dr. Russo, it should be used for:
  1. Consolidation following systemic therapy and good response
  2. Palliation
  3. Patients with the oligometastatic disease – if CN and metastasectomy will render patient disease free
  4. Non-clear-cell histologies in which systemic therapy may be less effective
She also highlighted the fact, that like others before have mentioned, the standard of care in CARMENA was sunitinib – which is no longer the standard of care in the modern era. Indeed, later today, even newer combinations of immune checkpoints and TKI’s are being presented with promising results. Hence, sutent alone shouldn’t be a comparison.

She made one last final point, which I thought was interesting – the only prospective proof of the benefit of CN was in the Flanigan et al. (J Urol 2004) data, which utilized an older, less effective immunotherapy (IFN-alpha)! Hence, there is a possibility that CN may actually have a role in the era of immunotherapy for mRCC.

Her final plugs were for some upcoming studies assessing this very question:

  • 1) PROBE – PI’s are Hyung Kim and Ulka Vaishampayan. The primary endpoint is OS. They are specifically assessing the need for CN in patients treated with upfront nivo/ipi followed by nivo maintenance. Study protocol is below:
UroToday_ASCOGU2019_Harshman, MD _2.png

  • 2) PROSPER RCC (EA8143) – PI’s: M. Allaf, L. Harshman, D. McDermott
In this study, they are assessing the role of pre-surgical priming with single dose Nivo followed by CN and systemic therapy (nivo maintenance) vs. CN alone. These are in patients with nodal disease only or oligometastatic disease – patients that don’t necessarily warrant systemic therapy off the bat. Study protocol below:

UroToday_ASCOGU2019_Harshman, MD _3.png

This is an exciting era of systemic therapies – but there is still a role for CN in selected patients!

Presented by: Lauren Christine Harshman, MD - Dana-Farber Cancer Institute

SUBMITTED BY: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

Further Related Content: Questions and Lessons Moving Forward from CARMENA: Which Treatment First? Surgeon’s Perspective

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