Kidney Cancer Take-Home Messages from ASCO GU 2020

Nuevo chico en el bloque: sitravatinib

Dr. Pavlos Msaouel de la Universidad de Texas MD Anderson Cancer Center, EE.UU. habló sobre los resultados de uno de los primeros ensayos clínicos de una combinación de un nuevo fármaco, sitravatinib, con nivolumab en personas con cáncer de riñón avanzado que ya habían sido tratados.

Sitravatinib es un tipo de medicamento llamado un inhibidor de la tirosina quinasa (TKI), que trabaja mediante la limitación del crecimiento de los vasos sanguíneos al tumor . Sitravatinib también puede funcionar haciendo que el tejido alrededor del tumor menos atractivo para las células cancerosas. Nivolumab es un inmune inhibidor de punto de control que se ha demostrado que funciona en el cáncer de riñón. Nivolumab libera los frenos ” en el sistema inmune permitiendo que las células del sistema inmune para matar las células cancerosas con más eficacia. Desde una combinación de estos dos fármacos parece funcionar bien en algunos otros tipos de cáncer, como el cáncer de vejiga, los investigadores pensaron que podría funcionar en el cáncer de riñón también.

“Funciona de la manera sitravatinib nos llevó a explorar si la inhibición de estas vías por sitravatinib puede inducir, mejorar o restaurar las respuestas a la inmunoterapia en pacientes con cáncer renal metastásico o localmente avanzado que previamente habían progresado en la inmunoterapia”, dijo el Dr. Msaouel. “Utilizamos nivolumab como la columna vertebral inmunoterapia y probado si combinación ist con sitravatinib produciría buenas respuestas en inmunoterapia resistente renal de células carcinoma ”.

El objetivo principal de este estudio fue determinar si los pacientes podían manejar a tomar los dos medicamentos juntos. Hubo 40 pacientes con cáncer de riñón en este estudio. Los efectos secundarios de la combinación de sitravatinib y nivolumab aparecieron manejable. El más común efecto secundario fue la diarrea, pero no era muy malo. Cuatro pacientes abandonaron el tratamiento debido a problemas con los efectos secundarios (sólo el 10% de todos los pacientes). Los investigadores también quería encontrar la mejor dosis de sitravatinib para pacientes con cáncer de riñón, y se encontró que una pastilla de 120 mg una vez al día dio los mejores resultados cuando se combina con nivolumab. Los investigadores están planeando un estudio de seguimiento más grande con esta dosis de sitravatinib y nivolumab.

Aunque los resultados son todavía muy temprano, la combinación de estos dos fármacos mostró alentar beneficios para los pacientes con cáncer renal avanzado que ya habían sido tratados con un TKI (como sunitinib y pazopanib ), sin demasiados efectos secundarios graves.

En caso de que el tumor de riñón original de ser removido de las personas con cáncer de riñón avanzado que están tomando la inmunoterapia?

Cirugía para extirpar el tumor de riñón es a menudo el tratamiento preferido para las personas con cáncer de riñón que no se ha extendido. Recientemente, los médicos han cuestionado si es beneficioso para operar para extirpar el tumor renal en pacientes con cáncer de riñón que ya se ha extendido más allá del riñón. En la mayoría de los otros tipos de cáncer que se han propagado, no se recomienda la realización de este tipo de cirugía. Se lleva todos los riesgos y las desventajas de la cirugía invasiva, pero por lo general no mejora la supervivencia. En lugar de ello, los fármacos antineoplásicos (por ejemplo, comprimidos, quimioterapia o inmunoterapia) han demostrado ser más beneficiosa.

Históricamente, el cáncer de riñón se ha considerado una excepción. Los ensayos clínicos de citoquinas, tales como interleuquina -2 y el interferón – alfa, a finales de 1990 mostró que las personas con cáncer de riñón avanzado tratados con citoquinas vivido más tiempo si tenían cirugía para extirpar el tumor del riñón, en comparación con aquellos que no lo hicieron.

En los 2000 de, citoquinas fueron sustituidos en gran medida por la terapia dirigida para el tratamiento de cáncer de riñón avanzado. Los ensayos clínicos de la cirugía, antes y durante el tratamiento con terapia dirigida mostraron claramente ningún beneficio de la extirpación del tumor renal.

A new family of immunotherapies for advanced kidney cancer include drugs such as nivolumab, ipilimumab, avelumab and pembrolizumab. These drugs work by releasing the ‘brakes’ on the immune system allowing the immune system to kill the cancer cells. These immune checkpoint inhibitor drugs are sometimes given in combination with targeted therapies that block the blood supply to the tumour. Many researchers and oncologists have questioned whether the old studies of kidney surgery for people with advanced cancer apply to today’s patients who have access to These new, and sometimes more effective medicines.

At the ASCO GU Cancers Symposium 2020, researchers from a large international research team known as the IMDC used data from people across the world to see whether surgery to remove the kidney tumour improved the lives of people taking immune checkpoint inhibitors.

They found that surgery was associated with improved survival in patients who took immune checkpoint inhibitors. However, the team stressed that these results do not apply to all patients with advanced kidney cancer. People taking immune treatment and surgery together are likely to be younger and have less medical problems. Because this was not a controlled study, these findings should be interpreted as preliminary only. Patients should decide very carefully if they are offered surgery, and in general, cancer medicines should be prioritised.

Radiation is safe, but does not improve immunotherapy in kidney cancer

New medicines for patients with advanced kidney cancer have improved rapidly in recent years, but many people need better outcomes, so research and clinical trials are more important than ever. Immunotherapy is one of these treatments.

Radiation has been used to treat cancer for over a century. Computers now enable radiotherapy to be focused so precisely, that it delivers a very high dose of radiation to a tumour, killing cancer cells but causing less damage to surrounding healthy tissues. Research in the laboratory has suggested that radiation might help immunotherapy by killing Cancer cells and making them more visible to the immune system.

Two clinical trials were presented at the ASCO GU meeting. First was the Phase II NIVES trial. In this trial, advanced kidney cancer patients who had been treated with targeted therapy were treated with the immunotherapy drug nivolumab and focused radiation. Radiation appeared safe with the immunotherapy, but people in the trial did not seem to benefit more than past studies of immunotherapy alone.

The second trial was the RADVAX RCC trial, which combined two immunotherapy drugs (nivolumab and ipilimumab) with focused radiation in patients with advanced kidney cancer. The benefit of adding focused radiation to the two immunotherapy drugs seemed at least equal to past studies of taking the two immunotherapy drugs alone and appeared safe.

Both these clinical trials enrolled small numbers of patients. In both trials, radiation was given to only 1-2 spots of cancer. These trials do not support immediate use of radiation with immunotherapy in people with kidney cancer, but they show that if radiation is needed, it is safe when taking immunotherapy. One situation where this might be useful is if one tumour starts to grow, while other spots of the cancer are shrinking due to immunotherapy treatment; “hunting down tumours that escape” seems like an attractive and sensible idea. Future trials will tell us if there are better ways of improving the benefit of immunotherapy in combination with radiation.

Moving up the chain to HIF-2α to block blood vessels in kidney cancer

Advanced kidney cancer is best treated today with the combination of either two drugs that unleash the immune system (immunotherapy; nivolumab and ipilimumab) or an immunotherapy drug (pembrolizumab or avelumab) plus a tablet that blocks blood supply to cancers (TKI; axitinib). These combinations of treatments help some people, but unfortunately the majority of people do not experience complete disappearance of their cancer. These people need further treatment, and most of the current options are of limited effectiveness.

Many kidney cancers (the clear cell type) grow many extra blood vessels. This is often because the machinery that controls blood vessel growth is broken. For the last decade or more we’ve had tablets that work at the end of this chain; tablets that end in -nib like sunitinib and pazopanib.

A new clinical trial was reported at ASCO GU using a new tablet that works further up the chain, closer to the breakdown. This link in the chain is called hypoxia-inducible factor, HIF-2α. A new tablet called MK-6482 blocks the action of HIF-2α. MK-6482 was tested in 55 patients who had taken several previous treatments for kidney cancer; most had taken at least three prior drugs.

In about one-quarter of people, their tumour significantly shrank in size, and in 80% of patients their cancer was controlled and didn’t grow while on treatment. People taking MK-6482 seemed to manage to tolerate the drug; only two people had to stop the treatment because of side effects. This result is promising enough that MK-6482 is being studied in a randomised trial compared against another drug used for kidney cancer; everolimus. If this bigger study is positive, MK-6482 could be a new treatment option for advanced kidney cancer patients who have tried other drug treatments but not been successful. As it seems to be well tolerated, it might also be able to be combined with other treatments like immunotherapy in the future.

POSTERS

Poster 767: Researchers are testing whether adding cabozantinib, a TKI for advanced kidney cancer patients, makes the nivolumab plus ipilimumab combination treatment work better in an ongoing clinical trial called COSMIC-313.

The COSMIC-313 trial was presented in a poster by Professor Toni Choueiri from the Dana-Farber Cancer Institute in Boston, USA. This study is looking for 676 people with advanced kidney cancer who are in poor health or whose cancer is growing fast (those at either intermediate or poor risk on the IMDC scale). The trial is looking for people who have not been treated with anything else before. Patients will be treated with nivolumab and ipilimumab together and then randomly allocated to take either a placebo tablet or cabozantinib. Neither the patient nor the doctor will know if they are receiving placebo or cabozantinib.

For each patient, the researchers will be assessing the time from starting treatment in the trial to when the cancer gets worse (progression-free survival) to determine the success of the trial. Researchers will also record all the side effects in this study to see which treatment is tolerated the best (nivolumab, ipilimumab, cabozantinib or nivolumab, ipilimumab, placebo). The trial is looking for patients now in North America, Europe, the Asia-Pacific region, and Latin America (https://clinicaltrials.gov/ct2/show/NCT03937219).

A scan shows a mass on your kidney – is it cancer? Or something less aggressive? Poster 623 looked at the use of a biopsy; removal of a small piece of the kidney mass with a needle to look at the cells under a microscope to see if they are cancer. The question being asked was whether taking a biopsy reduced over treatment in people found to have a benign, less aggressive mass called an oncocytoma. The researchers followed 170 people with proven oncocytoma. Seventy percent (70%) had been diagnosed using a biopsy and after biopsy almost all people (93.4%) chose to take active surveillance; no surgery, just watch the lump with scans and doctor’s appointments. On average, these oncocytoma grew only 1mm per year, though a quarter of people had growth at a rate >5mm per year. Less than 10% of people chose to have an operation after starting surveillance, and no-one had spread of their cancer. Biopsy reduces the use of unnecessary surgery and its side-effects for benign renal masses, such as oncocytoma. The information from this study gave us further information about oncocytoma and supports the use of active surveillance as a safe Management option, which can reduce the harm caused by over treatment.

Poster 637 reported on a group of patients facing one of the toughest situations; their kidney cancer had spread into the brain. This was a real-world report of 17 patients with advanced kidney cancer in the brain. The patients were treated with ipilimumab and nivolumab combination immunotherapy. For a lot of people, the treatment wasn’t successful. However, some people benefited from combination immunotherapy treatment. Forty-two percent (42%) of people had shrinkage of their tumour (though no-one saw cancers disappear completely) and another 29% had stable disease where their cancer stopped growing. Only about 20% of people did not respond to treatment and their cancer continued to grow. The amount of treatment, and the amount of side-effects was similar to that seen in other clincial trials with the combination immunotherapy treatment. Of note, 50% (3/6) patients treated with this combination after failing to respond to another treatment had tumour shrinkage.

In relation to this, Poster 687 looked at another trial of two drugs called avelumab and axitinib (JAVELIN Renal 101 trial; an immunotherapy and TKI). Some people on this trial had kidney cancer that had spread to the brain, and the combination of drugs might have helped People more than taking a TKI tablet (sunitinib) alone. People with kidney cancer that has spread to the brain still face a very tough path, but these very small reports give some hope that new Treatments might even help in this very difficult situation.

Poster 642 presented data from the International Metastatic RCC Database Consortium (IMDC) looking at the question of what happens to people if their kidney cancer spreads to specific parts of the body. If a cancer spreads to brain, liver or bones, that is generally a worrying situation in most cancers. Spread of the cancer (metastases) to organs that make hormones (endocrine organs like the pancreas, thyroid, adrenal) are infrequent but this study showed that people with this pattern of spread had the longest median overall survival. The study confirmed what is seen in most cancers; bone, liver and brain metastases were associated with a shorter survival. Understanding these patterns is useful for patient counselling about treatment options and for designing new clinical trials.

Poster 655 used a different database called REMARCC (Registry of MetAstatic RCC) that follows people with advanced kidney cancer. Four hundred and forty seven (447) patients with or without bone metastases were included in the analysis. The authors concluded that presence of bone metastases does not independently predict survival or outcomes in advanced kidney cancer. This is at odds with the IMDC poster above; this is an important area of ongoing study.

Poster 686 reported on a very rare group of people with metastatic fumarate hydratase (FH) deficient renal cell carcinoma (RCC), a rare metabolic variant of RCC. The authors reported on the experiences of 32 patients with FH-RCC showing a distinct pattern of disease course with immediate spread around the kidney into the space between organs inside the abdomen (the peritoneal space). People with FH-RCC had a high chance of response to targeted therapy combinations (e.g. VEGFR/mTOR Inhibitor combinations; lenvantinib + everolimus), but there were limited responses to immune checkpoint inhibitiors, at least when given as a single drug like nivolumab or pembrolizumab.

Finally, Poster 707 reported on a question we would have thought incredible only a few years ago; if you have kidney cancer that has spread from the outset, you take combination immunotherapy and all the cancer spots on your scans completely disappear, and all that remains is the original spot in the kidney… should you then have an operation to remove the primary kidney cancer? Is it worth the risk of an operation to be able to say that the scans are all clear?

This poster reported the challenges of nephrectomy after complete response to immune checkpoint inhibitors for metastatic renal cell carcinoma. Eleven patients who had not had surgery at diagnosis were included in the study. The operations were perhaps more difficult, and one patient died of post-operative complications, but live cancer was still found in most patients. The authors concluded that surgery to remove the primary kidney cancer following combination immunotherapy could allow people to have a “complete response” in selected patients. Due to technical complexity and complication rates, this surgery should be performed in centers with extensive experience. Although only a small number of patients were investigated, this study looked at a new treatment pattern, and more data on surgical safety are needed.

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