Video Traducido al Español sobre los mas asombroso y determinante de ASC0 2023

Leer la discusión en Español:

Hola a todos, soy Rahul Gossand y soy Roy Gosane, y somos los Hermanos Oncólogos. Hace apenas unos días, se presentaron cerca de 6.000 resúmenes en ASCO 2023, centrándose en lo que está cambiando la práctica o informando en el ámbito del cáncer de mama. Hemos seleccionado tres estudios: el ensayo Natalie en el entorno adyuvante, el ensayo Sonia y el ensayo X7.7 en el ámbito metastásico, para revisar estos estudios críticos. Nos acompaña la renombrada oncóloga médica especializada en cáncer de mama, la Dra. Stephanie Graff. ¡Bienvenida Dra. Graff!

Dr. Graff: Gracias por recibirme, fue genial verlos en ASCO y es un placer estar aquí con ustedes hoy. Conocer a tantas personas y aprender tanto es lo mejor de ASCO. Wow, ha sido un fin de semana increíble. Todavía me siento abrumado por todos los datos que se presentaron en ASCO 2023.

Comencemos hablando del ensayo Natalie, pero antes de eso, es importante establecer y discutir cuál es el estándar de atención actual. En pacientes con cáncer de mama receptor hormonal positivo en la configuración adyuvante, el estándar de atención es el uso de un inhibidor de CDK4/6 junto con terapia hormonal. También se actualizaron los datos sobre el inhibidor de CDK4/6 en ASCO 2023, donde se demostró su beneficio tanto en pacientes menores de 65 años como en pacientes mayores de 65 años, e incluso aquellos que tuvieron reducción de dosis también obtuvieron beneficios sostenidos. Ahora tenemos datos del ensayo Natalie que evalúa el uso de ribociclib en la configuración adyuvante. Dra. Graff, ¿cuál fue el diseño del estudio y los criterios de inclusión?

Dr. Graff: El ensayo Natalie aleatorizó a pacientes con cáncer de mama en etapa temprana para recibir ribociclib en combinación con terapia hormonal versus terapia hormonal sola. La terapia hormonal utilizada fue inhibidores de aromatasa no esteroideos, específicamente letrozol o anastrozol para pacientes premenopáusicas o hombres que tuvieron supresión de la función ovárica para ser elegibles. Fue un esquema de aleatorización de uno a uno. Es importante destacar que los criterios de elegibilidad en el ensayo Natalie eran un poco más amplios que los del ensayo Monarche, por lo que se trató de una población de riesgo ligeramente menor. En resumen, Monarche incluyó pacientes con enfermedad N2 o N3, así como un pequeño grupo de pacientes con enfermedad N1 y factores de riesgo adicionales, como tumores T3, tumores de grado 3 o un índice de proliferación ki-67 superior al 20%. Por otro lado, Natalie incluyó pacientes con enfermedad N1, así como todos los pacientes con enfermedad N2 y N3. Natalie también incluyó algunos pacientes con enfermedad N0 específicamente T2 y N0, y cualquier paciente en etapa tres, incluso si era etapa tres con enfermedad N0. En el caso de los pacientes con T2 y N0, debían tener otro factor de riesgo, como un tumor de grado 2 con un índice de proliferación ki-67 superior al 20% o un tumor de grado 2 con un alto puntaje de oncotipo de riesgo u otro modelo de riesgo genómico alto, como el mammaprint. Por lo tanto, se debía cumplir uno de esos criterios para ser elegible para el ensayo Natalie. El objetivo principal fue la supervivencia libre de enfermedad invasiva, y se demostró una reducción absoluta del 3,3% y una reducción del riesgo relativo del 25,2% después del seguimiento medio. Esto es similar a lo que vimos en Monarche en el mismo punto de tiempo. Por supuesto, debemos tener cuidado al hacer comparaciones entre ensayos, ya que no es adecuado hacerlo. A largo plazo, creo que la Dra. Nadia Harbeck, en su análisis, señaló que esto crea dos estándares de atención para el tratamiento adyuvante del cáncer de mama en estadio temprano. Estoy de acuerdo con ese sentimiento. Ahora entramos en esa sutileza y en la atención clínica de nuestros pacientes. En mi caso, prestaré atención a quiénes hubieran sido elegibles para Monarche y quiénes hubieran sido elegibles para Natalie. Para los pacientes que se encuentren en esa área de superposición y sean elegibles para ambos ensayos, consideraré aspectos como la madurez de los datos y cuánto podría importarle al paciente con el que esté hablando. Hay pacientes para los que eso es un factor importante, así como los efectos secundarios de los dos medicamentos y las interacciones farmacológicas. Gracias por repasar eso.

Rahul: Es importante ver

 cómo estamos comenzando a utilizar dosis más bajas en lugar de buscar la dosis más alta cuando sabemos que podría haber beneficios y, nuevamente, centrarnos en la calidad de vida es tan importante tanto en el entorno metastásico como en el adyuvante. Y seguimos viendo esto, pero como oncólogo médico general, Dra. Graff, también ha tocado este tema en su trabajo. Ahora estamos viendo diferentes dosis aprobadas para diferentes cosas, diferentes recomendaciones. Es tan importante para nosotros estar al tanto de eso, no solo de las aprobaciones de medicamentos, sino también de la dosificación de los medicamentos día a día cuando vemos a estos pacientes. Es realmente difícil si tienes que verificar cada vez, pero creemos que eso es por lo que hay tantos controles y equilibrios en lo que hacemos. Y solo para agregar a esto, en el caso de ribociclib, estamos usando el tratamiento durante un total de tres años, mientras que en el caso de abemaciclib, es de dos años. Y no puedo enfatizar lo suficiente que todos debemos estar involucrados, incluido el paciente también.

Roy: Exactamente, tantos matices, al menos en mi práctica, anticiparía que para los pacientes sin ganglios afectados, por supuesto, preferiré ribociclib, pero para la enfermedad con ganglios afectados, habrá mucha discusión en términos de los efectos secundarios y el fármaco y cuál es el fármaco adecuado para el paciente que tenemos frente a nosotros. Sí, este estudio fue en el ámbito del cáncer de mama temprano. Ahora cambiemos de tema y nos centremos en el segundo estudio, que es en pacientes metastásicos con receptor hormonal positivo. El estándar de atención actual para estos pacientes ha sido el uso de inhibidores de CDK4/6 con inhibidores de aromatasa, pero este estudio desafía eso y plantea que solo unos pocos pacientes pueden recibir inhibidores de aromatasa solos. Dra. Graff, ¿podría comenzar hablando sobre el diseño del estudio y luego profundizaremos en los hallazgos?

Dr. Graff: El estudio Sonia es un estudio muy bien diseñado y pragmático, realizado y financiado por los Países Bajos, que busca responder qué debemos hacer con la secuenciación. ¿Todos necesitan un inhibidor de CDK4/6 en la primera línea? El estudio incluyó a todos los pacientes con cáncer de mama metastásico receptor hormonal positivo sin evidencia de crisis visceral y los aleatorizó uno a uno si no habían recibido previamente terapia para el cáncer de mama metastásico. Se les asignó aleatoriamente recibir inhibidor de aromatasa más inhibidor de CDK4/6 seguido de fulvestrant, lo que llamaremos el grupo de tratamiento estándar, porque eso es lo que se hace actualmente en los Estados Unidos, o recibir inhibidor de aromatasa en primera línea seguido de fulvestrant más inhibidor de CDK4/6. Lo que vimos fue que el criterio de valoración principal de este estudio es lo que han denominado supervivencia libre de progresión 2 (PFS2), que es la supervivencia libre de progresión después del cambio de tratamiento. La supervivencia global es neutral, con una supervivencia global mediana de 45,9 meses para los pacientes que recibieron inhibidor de CDK4/6 en primera línea y 53,7 meses para los pacientes que recibieron inhibidor de CDK4/6 en segunda línea. El hazard ratio se encuentra alrededor del umbral mágico y el valor de p bilateral es de 0,83, lo que indica que las líneas no son muy diferentes y se considera neutral. Es importante destacar que la PFS1 mostró que los pacientes se desempeñaron bastante bien con un inhibidor de CDK4/6 en primera línea durante 24,7 meses, pero también se desempeñaron muy bien con un inhibidor de aromatasa en primera línea, lo cual es más de lo que esperaríamos clásicamente. Es difícil para mí saber si esto se debe a la homogeneidad de la población de los Países Bajos en comparación con las poblaciones globales que participaron en los estudios de inhibidores de CDK4/6. Además, el inhibidor de CDK4/6 utilizado en este estudio fue principalmente palbociclib. Por supuesto, sabemos que ribociclib ha demostrado supervivencia global y abemaciclib está muy cerca de cumplir ese objetivo. Por lo tanto, es difícil saber cómo el hecho de que palbociclib sea el inhibidor de CDK4/6 utilizado en este estudio afecta nuestra interpretación de los datos. A medida que interpreto estos datos y hago cálculos, creo que los pacientes que recibieron un inhibidor de CDK4/6 en primera línea también tuvieron buenos resultados con fulvestrant como agente único. Hay muchas cosas que son diferentes en este ensayo y esta población de pacientes en comparación con lo que vemos hoy en nuestras poblaciones estadounidenses. Además, diría que el estándar de atención en segunda línea en este momento no es fulvestrant. Realmente hacemos secuenciación genómica, por lo que no sé si decir que un inhibidor de CDK4/6 seguido de un inhibidor de aromatasa versus un inhibidor de aromatasa seguido de un inhibidor de CDK4/6 es realmente lo que se ve en la práctica hoy en día. En el contexto de la atención médica en Estados Unidos, creo que el ensayo Sonia es importante, pero difícil de implementar. No creo que esto cambie nuestro estándar de atención actual en la primera línea, pero sin duda nos hace reflexionar sobre la secuenciación y si todos los inhibidores de CDK4/6 son iguales, lo cual es una discusión aparte.

LEER TEXTO EN INGLES

 hello everyone I am Rahul gossand and I'm Roy gosane and we are oncology Brothers just days ago close to 6 000 abstracts were presented at ASCO 2023 focusing on what is practice changing or informing in breast cancer Arena we've selected three studies Natalie trial in adjuvant settings and then Sony a trial and x77 and metastatic space to go over these critical studies we're drawn by a renowned breast medical oncologist Dr Stephanie Graff Dr Graf welcome thanks for having me it was great to see you guys at ASCO and it's great to be uh here again with you today yes it was certainly nice meeting everyone that's the best part about ASCO and learn so much wow what a weekend it has been I feel I'm still in days from all the data that was presented at ASCO 2023 to get started we're going to jump into Natalie trial but before we get started with that it is important to establish and discuss what is the current standard of care that is a bemocyclit in early hormone receptor positive patient population in adjuvant setting in high risk patients now a Bama cyclip data was also updated at ASCO 2023 where we saw the benefit in less than 65 year old patient population and uh above 65 year old patient population and then importantly patients who had dose reduction also had sustained benefit now we have data from Natalie trial looking at ribosyclip in adjuvant setting Dr Graf what was the study design and the inclusion criteria here so the Natalie trial randomized patients with early stage breast cancer to ribosiklib in combination with hormone therapy versus hormone therapy alone though hormone therapy that was used was the non-steroidal aromatase Inhibitors so only letrozole or Anastrozole pre-menopausal patients or men had to have ovarian function suppression in order to be considered eligible and it was a one-to-one randomization scheme now the Natalie trial importantly has slightly broader eligibility criteria than monarchy so it's a slightly lower risk population um in short monarchy took patients that had N2 or N3 disease and a small population of patients that had N1 disease and additional risk factors T3 tumors grade three tumors or a ki-67 of greater than 20 percent Natalie took all and one disease also all N2 and N3 disease Natalie also took some and zero disease specifically T2 and zero disease um and then anybody that was stage three um even if they were stage three with n0 disease um if you were a T2 and zero you had to have another risk factor and that included either um a grade 2 tumor with a ki-67 of greater than 20 percent or a grade 2 tumor with a high risk oncotype score or um other high genomic risk model like a mamma print um and so you had to meet one of those criteria in order to be eligible for Natalie um primary endpoint was invasive disease-free survival and showed that uh the reduction in um invasive disease-free survival was an absolute reduction of 3.3 percent and a relative risk reduction of 25.2 percent after the median follow-up now this is similar to what we'd seen in Monarch e at about the same time Point um of course the dangerous cross-trial comparisons we don't do that um long term of course I think that I agree Dr Nadia harvack was the discussant and she ended her discussion by saying that she thinks this creates two standard of cares for the early uh the adjuvant treatment of early uh stage breast cancer I agree with that sentiment um of course now we get into that nuance and our clinical care of patients for me I will pay attention to who would have been eligible for Monarch E versus who would have been eligible for Natalie for patients that are in that Venn diagram of overlap that are eligible for both um I'm going to be thinking about things like the maturity of the data and how much that might matter to the patient that I'm sitting with there's some patients that that's an important factor the side effects of the two drugs the drug drug interactions of the two drugs thank you for going over that just to retreat it is so important to see this where we are starting to use lower doses rather than chasing the highest dose when we know there could be benefit and again focusing on quality of life is so critical in metastatic and of course accurate settings and we continue to see this but as a general medical oncologist Dr Graf you've touched upon this on your end as well now we're seeing different doses being approved for different things for different recommendations it is so important for us to keep on top of that not only the drug approvals but also the drug dosing day in day out when we're seeing these patients no it's really hard if you if you double check your check every time believe that that's why there's so many checks and balances in what we do and just to add there in ribosite club we are using the therapy for a total of three years while a Bama cichlid is two years and I can't reiterate that we need to all be involved including the patient as well yes exactly oh my gosh so many nuances right yeah at least uh in my practice I anticipate that for no negative patients of course who will favor ribo but for no positive disease there's going to be a lot of discussion in terms of the side effects but agent and what's the right drug for the patient in front of us yeah so this study again was an early breast cancer science now let's switch gears and focus on second study which is a metastatic hormone receptor positive patients the current standard of care for these patients has been cdk46 Inhibitors with AI but this study challenges that selective few patients can get AI alone Dr Graf can we start off with the study design and then we'll dive into its findings yeah so the Sonia study is a very well designed very pragmatic study conducted and funded by the Netherlands to ask what should we be doing about sequencing does everybody need a cdk46 inhibitor in the first line um it took all patients with metastatic hormone receptor positive Advanced Breast Cancer without evidence of visceral crisis and randomize them one to one if they were had no prior therapy for metastatic breast cancer to either AI plus cdk46 inhibitor followed by a full restaurant which we're going to call the standard of care arm because that's what our current practices in the United States versus first line aromatase inhibitor followed by fullvestrant plus cdk46 inhibitor and what we see is that the primary endpoint of this study is what they have labeled PFS 2 which is the progression-free survival after this after the switch overall survival is neutral right the median overall survival shows us the patients that got a first-line cdk46 inhibitor had a median overall survival of 45.9 months patients who got a second line cdk46 inhibitor had a median overall survival of 53.7 months on the hazard ratio is you know crossing the magical threshold the two-sided p-value is uh you know 0.83 and these lines are not all that different and so this is considered neutral the notably the PFS one um did show that patients did pretty well with a first-line cdk46 inhibitor at 24 um points uh seven months but they also did really well with the first line aromatase inhibitor um which is maybe a little bit more than what we would classically expect it's hard for me to know if that's related to the homogeny of the Netherlands population versus the global populations that have been accrued to the cdk-46 inhibitor studies um Additionally the cdk46 inhibitor used in this study was by far and away Paulo cichlid um of course we know that ribosiklib has met overall survival a bemocyclib is dangerously close uh trending that way uh and Palo cichlid did not meet its overall survival endpoint so how the fact that palbo cichlid is the cdk-46 inhibitor uh factors into our interpretation of this data um is unclear um as I interpret this data when I when I kind of take a step back and do the math I think that patients who got a first line cdk46 inhibitor also did really good on fullvestrant as a single agent so there's lots of things that are just different about this trial and this patient population than that maybe translate to what we're seeing today in our U.S populations additionally I would say that the second line standard of care right now arguably is not Sylvester in it we do genomic sequencing so I don't know that to say that that cdk46 inhibitored followed by AI versus AI followed by cdk46 inhibitor is really what our options look like today so on the grander scheme of things this is a complicated study to interpret in the context of American Health Care I think that the Sonia trial is important I think it's hard to put into play in the U.S and again I don't think this by any means at least here changes our standard of care in first line but certainly a food for thought saying hmm sequencing versus is it all just different cdk4 sex Inhibitors which of course is a conversation on its own so yeah as we're discussing metastatic disease this is a good segue into our next study X 7.7 looking at Cape cider being in our metastatic breast cancer patients population topograph if you don't mind walking us through the study design here so this study x7x7 was led by Kamar Khan who's my of my mentors and I'm so proud of him in this work because it's again such a pragmatic study that just needed to be done right like who like of course we needed to know this um and it took patients with metastatic breast cancer of any biology hormone receptor positive triple negative her2 positive her two positive patients received the cape with tres tuzumab and patients were randomized one to one um at any line of treatment whether they you know first second whatever um to either fixed dose Cape cyta Bean or standard dosed Cape cyta Bean they were stratified by very rational things the type of breast cancer the line of chemotherapy that they were on so we we have very matched cohorts in a very heterogeneous population which I think is important fixed dose Heap cytobine for this population is defined as keep setting at fifteen hundred milligrams full stop not milligrams per meter squared milligrams Keo twice a day for seven days in a row followed by a seven day break so every other week the standard dose is described as keeps cited being 1250 milligrams per meter squared did you hear it um twice a day 14 days on one day off um so patience what we saw as we moved into the results that received the standard dose as compared to the fixed dose patients had very similar progression-free survival um Dr Khan did do a landmark analysis where he assessed that um those median the progression-free survival at 12 24 and 36 months and the fixed dose over time shows um it it favors the fixed dose so patients stay on the fixed dose longer patients that were on the fixed dose had a much lower toxicity which was actually Stark and dose reductions were also much much more common in the standard dose set um now I want to comment here that of course this was all a metastatic population I do not think that this extrapolates to using cake cyta bean in the createx population but overall I think that this x7x7 trial is practice changing or at least practice informing um do I think that every patient should get fixed dose Cape cytamine maybe not do I think that you can feel very comfortable altering your cape citing dosing particularly in patients that you are otherwise concerned about and give them this fixed dose absolutely um to Dr Khan's Point as he was introducing the concept of course the long Legacy of medical oncology is that we just do drug Discovery based on maximal tolerated dose not um maximal efficacious dose and so it's been long unclear what dose of Cape citibine actually works for breast cancer and this has shown that a lower fixed dose of Cape cytobean appears to offer good efficacy again coming back to the same theme we're seeing lordosis we talked about this ribo Obama and now here for Cape site to being this is um the this is definitely kind of practice um this will change the way that I prescribe Cape said to be and I will I will be more lenient on my dosing and additionally to add to this is the side effect profile which is diarrhea hand foot syndrome that we continue to see and just to dive in which was also presented detorch which is again small changes rather nominal cost changes where utilization of topical diclofenac reduce the amount of symptoms that these patients were incurring yeah I completely agree so detorch looked at diclofenac gel the prescription was one gram one percent topical gel bid so twice a day on your hands presumably you could apply it to your feet but the trial was to your hands um for the first four cycles of and it showed a significant reduction in the risk of hand foot syndrome um and a significant reduction in the rate of Cape cytobean dose reduction as well so um I agree I think that that's practice changing what an innocent intervention to offer somebody and I I think I mentioned or like low attention poster that I that I thought was interesting was there was a poster that showed that taking tamoxifen at night um rather than in the morning significantly prolonged disease-free survival with a hazard ratio of 0.43 um certainly I don't think that um that I mean how what an easy intervention right to tell your patients to take tamoxifen at bedtime instead of in the morning and I think all of us sometimes try that to get people's side effects to change anyway so um uh Food For Thought only worked with tamoxif and not the AIS but um switching it to nighttime dosing for tamoxifen also seems like low hanging fruit to make a potential inner prevention and the outcomes of our patients absolutely and this is not just quality of life this was rather survival which is very impactful yeah Dr Graf thank you so much for taking the time to go where these critical studies and breast cancer that were presented at ASCO 2023 to say the least these some of these are certainly practice informing and practice changing stay tuned for a quick summary and take on points Dr Graf thank you so much again we just wrapped up our interview with Dr Stephanie Graf where we covered three important studies Natalie trial with riboscyclip x7x7 evaluating the frequency of Cape cyta Bean Sonia trial looking at sequencing of cdk-46 Inhibitors question becomes how are we planning to incorporate this data in our practice tomorrow so first Natalie trial we have to wait under approval to come which is very likely to happen but this will give us an option of using another cdk46 inhibitor ribocyclobin in select node negative and Beyond when it comes to breast cancer which again is a broader indication than the current of democycle of approval agreed well we have to keep in mind some nuances here that is ribosyclip was utilized for three weeks on one week off at 400 milligram dosing which is different from metastatic setting which is 600 milligrams and here the dose was utilized for a total of three years time in Monarch E A Bama cyclobin adjuvant setting one is to take the medication daily for a total of two years time and both of them have a different side effect profile absolutely and then uh x7x7 where we used a fixed dosing of Cape cytopene seven days on seven days off this was better tolerated than the current standard dose that we tend to use for tape site to Bean this study did not compromise outcomes so patient tolerated the treatment better and had similar outcomes that we tend to see with standard of care in conjunction to this with hand foot syndrome which we often see with cape cyta Bean a study detorch showed that topical diclofenac improves the side effects especially hand foot syndrome significantly absolutely and then we've also covered Sonia trial where we saw that selected patients can maybe just get AI alone that selected patient could be a frail patient who's sitting in front of you but again to reiterate right now this perhaps does not change the current standard of care of cdk-46 Inhibitors and AI in Frontline settings well that's a wrap stay tuned for more next time for the oncology Brothers 

https://www.youtube.com/watch?v=P7rWK9HV074&list=PPSV