ESMO 2018: 'Tremendous Advances' in Breast Cancer Treatment

Hope S. Rugo, MD; Giuseppe Curigliano, MD, PhD; Fatima F. Cardoso, MD


November 07, 2018

Hope S. Rugo, MD: Hello. I'm Hope Rugo, professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco's Comprehensive Cancer Center. Welcome to Medscape Oncology Insights, coming to you from the 2018 Congress of the European Society for Medical Oncology (ESMO).

Today we'll be discussing some clinically relevant highlights from the breast cancer data presented at this meeting. I think we would all agree that this meeting had some of the most exciting data we have seen in breast cancer in some time. Joining me are my colleagues and friends Dr Fatima Cardoso and Dr Giuseppe Curigliano. Fatima is director of the Breast Unit at the Champalimaud Clinical Centre in Lisbon, Portugal, and is also very much involved in the organization of the meeting, as is Giuseppe, who is chair of the Division of Early Drug Development at the European Institute of Oncology and associate professor at the University of Milan, Italy.

ESMO 2018 might have had the biggest amount of breast cancer data ever. We heard very exciting data from the first positive immunotherapy trial in breast cancer for triple-negative breast cancer (TNBC), the IMpassion130 trial[1] with atezolizumab plus nab-paclitaxel. And we heard some fascinating data in the hormone-receptor-positive field where we are making tremendous advances. Of the trials that we saw at the meeting, IMpassion130 probably has the biggest chance of changing treatment practice in the very near future. Giuseppe, please tell us a little bit about the trial design of IMpassion130 and the study data.

IMpassion130 Study

Giuseppe Curigliano, MD, PhD: I believe IMpassion130 is bringing breast cancer into the immunotherapy era. It was a prospective phase 3 trial with almost 900 patients who were randomized to receive nab-paclitaxel plus atezolizumab versus nab-paclitaxel plus placebo. There was an improvement in progression-free survival (PFS) and improvement in overall survival (OS) in patients with programmed cell death ligand 1 (PD-L1)-positive breast cancer. We could discuss the assessment of PD-L1 because the companion diagnostic developed by Roche/Genentech is assessing PD-L1 on immune cells rather than tumor cells. It is quite clear that 25 months of OS in the experimental arm is not trivial. But there are questions. Will this trial be practice-changing? I believe it will because it demonstrates that immunotherapy may work in a TNBC population if we select patients according to specific features. Second, is this the right way to develop immunotherapy in breast cancer? Maybe we need to wait for the data from neoadjuvant setting where pathologic complete response (PCR) is the primary endpoint and where there is the opportunity to discover much more in terms of predictive biomarkers.

Rugo: As we have been involved in the study and have seen the data roll out over the summer until its presentation here, it was really interesting to see that the PFS difference—even in the PD-L1-positive cohort—was only 2.5 months, which mostly we kind of sniff at when an expensive new drug is being added in. For TNBC, 2.5 months median may still be clinically important. But the OS difference of almost 10 months is quite striking. We don't often see that differential in PFS versus OS. Do you have a thought or hypothesis about where that is coming from?

Curigliano: In immunotherapy, it is quite common—also in other diseases—to see a very small improvement in PFS and a significant improvement in OS, because you activate the immune system and then you can have a delayed effect. You induce mutagenic cell death with the first-line chemotherapy, and after immunotherapy administration, the carryover effect of immunotherapy can persist for several months. In other diseases, when you use an immune checkpoint inhibitor, you can see response after several months. This is a typical effect of immunotherapy, I believe.

Rugo: It's also interesting because in the CLEOPATRA trial[2] that added pertuzumab to trastuzumab, the PFS difference was longer—6.5-6.7 months or so—but the survival difference was 15.7 months. So maybe antibodies affect the immune microenvironment in a way, even if it's HER2 targeted, and maybe their effect is also immune. It is encouraging to see that atezolizumab added to nab-paclitaxel is fairly well tolerated. Immune toxicity was at the same low rate that we have seen in other studies. The drug may get approved for the breast cancer indication sooner than, say, alpelisib because it's already an approved drug and adding indications is faster. One question that may come up is whether you have to partner it with nab-paclitaxel. Fatima, when this becomes available, will you feel like you have to give it with nab-paclitaxel or could you give it with the cheaper paclitaxel?

Fatima F. Cardoso, MD: I hope we can answer that question soon because it would mean making something that is already expensive even more expensive. I hope ongoing trials will show us that we can combine immunotherapy with other types of chemotherapy in breast cancer. I also want to make the point that IMpassion130 is a very well-designed trial. I always fight for OS to be a co-primary endpoint, and I wanted to acknowledge that this is a trial where PFS and OS are co-primaries and that is very important.

Rugo: As you pointed out, we are going to see data from other trials in the metastatic setting with paclitaxel, gemcitabine, and carboplatin, and there are also several randomized trials in the neoadjuvant/adjuvant setting with checkpoint inhibitors. We will see a lot of data.

PALOMA-3 Study

Rugo: That is a perfect lead-in for discussing the first survival data we've seen from a phase 3 trial with a cyclin-dependent kinase (CDK) 4/6 inhibitor. CDK 4/6 inhibitors rapidly became a standard of care in combination with first- or second-line endocrine therapy for the treatment of metastatic hormone-sensitive breast cancer. It's really been amazing how quickly they have been incorporated into most treatments when available. Even with this doubling of PFS, we have been missing the survival data. We saw from the first trial that reported PFS data, now the first survival data. Tell us a little bit about PALOMA-3.

Cardoso: PALOMA-3[3] is a phase 3 trial that assessed the role of adding palbociclib, a CDK 4/6 inhibitor, to fulvestrant as mostly a second-line treatment. We saw at this meeting the first presentation of the OS results. Unfortunately, it didn't reach statistical significance. However, I don't think we can dismiss 6.5 months benefit in OS that is almost statistically significant. It points out something we have been fighting for: Trials should be designed to be sufficiently powered to see an OS result. What changes the life of advanced breast cancer patients is impact on survival. Nevertheless, these results establish an even stronger [role for] CDK 4/6 inhibitors in the management of ER+/HER2-negative disease, together with the facts that they are very well tolerated and there is substantial improvement in quality of life and delayed deterioration of the same quality of life, particularly in the second-line setting. All of that together makes them an extremely good option to use. I'm always careful to say "standard of care" because once we say that something is the standard of care, every trial from then on has to have it in the control arm. I don't think we need to do that in the field of breast cancer, so it's one very favorable option to use for our patients.

Rugo: I think CDK 4/6 inhibitors will be the comparator for all trials going forward, certainly in the first- and second-line settings, because of their widespread use. It's going to be hard not to have them. In fact, some trials are really struggling over whether to require them as prior treatment since they are not available in all countries. You started our advanced breast cancer guidelines group which we've been involved with, and it's a tremendous addition to our guidelines[4] and to the whole approach to breast cancer. Also, I have worked with the Metastatic Breast Cancer Alliance, which is trying to help make treatments available worldwide; of course, if we increase the cost of drug development then drugs will be even more expensive.

Cardoso: I actually disagree with you. I don't think we will increase the cost by increasing [trial enrollment by] a few dozen or a few hundred patients. We can save a lot of money by not running trials that don't reach any conclusion. I was fortunate enough to discuss this at the Presidential Session and I gave some examples of trials that were a waste of resources. Let's focus on fewer numbers of trials but very well-designed and -powered ones so that we can really move the field forward.

Rugo: Giuseppe, PALOMA-3 also looked at hormone-sensitive versus non-hormone-sensitive disease, and they showed that the survival benefit was almost 10 months in patients with hormone-sensitive disease. Does that impact your treatment practice?

Curigliano: It is quite complex in a trial designed for endocrine-resistant disease to define within endocrine resistance the most sensitive patients. In any case, time to treatment failure was used to define the most sensitive population, and similar data have been described with abemaciclib. It's quite common that patients who derive a longer period of benefit from endocrine therapy may also derive much more benefit from agents like CDK 4/6 inhibitors because they are more sensitive. If you change the endocrine therapy to overcome resistance usually related to ESR1 mutations, fulvestrant can overcome this alteration. That is why I believe you have much more benefit in this subpopulation of patients.

Rugo: We are making great advances in treating hormone receptor–positive disease and we hope that translates into improved cure rates for early-stage disease. We have more than 15,000 women being randomized on adjuvant CDK 4/6 inhibitor trials but we know that almost 50% of them with hormone receptor–positive tumors have mutations in phosphatidylinositol-3 (PI3)-kinase. We saw results from the phase 3 SOLAR-1 trial at the Presidential Symposium with the alpha-specific PI3 kinase inhibitor, alpelisib. Tell us a little bit about that trial.

SOLAR-1 Study

Curigliano: SOLAR-1 was a very well-designed trial because this is the first precision medicine biomarker-driven trial in the field of metastatic breast cancer. Patients with endocrine-resistant disease were randomized to receive the alpha-selective PI3 kinase inhibitor, alpelisib, plus fulvestrant versus fulvestrant/placebo. We had two cohorts of patients: one cohort with PI3 kinase-mutated breast cancer, and one cohort with no mutations. So we also validated the effect of the drug in the cohort of patients without mutations as well. There was an increase in PFS that I believe was significant of 10.5 months versus 3.7 months in the control arm. And there was a benefit in terms of response rate: 35% response rate in the combination. There was talk about toxicity, and this may be a concern. Almost 60% of patients had hyperglycemia. Fifteen percent of patients experienced grade 3/4 and metformin was mandatory for them. Diarrhea was also observed. I believe alpelisib is an option for some patients who are progressing on CDK 4/6 inhibitors and that may harbor a PI3 kinase mutation on the primary tumor or on the metastatic disease. I believe we should consider alpelisib if approved in this specific subpopulation of patients. Then we need to answer the question about sequence of endocrine therapy. This is also a question for the International Consensus Conference for Advanced Breast Cancer (ABC) meeting.

Rugo: The almost-doubling of PFS at 11 months versus 5.7 months is very impressive. And we've seen that with other agents, like everolimus. One of the issues is going to be balancing toxicity when 25% of patients discontinued for toxicity. Although 75% discontinued for disease progression, so that's still the biggest reason people stop. We found that management of the toxicity upfront and education make a big difference; the discontinuation rate for adverse events was dropping throughout the trial.

Cardoso: The same happened with everolimus. I think the more we educate and the more we learn how to manage side effects, the more manageable these drugs become. Because the majority of patients are treated in the community, we really need to emphasize the problem of toxicity and teach physicians, nurses, and patients how to manage the toxicities upfront.

Rugo: Very few patients received CDK 4/6 inhibitors in a trial. We have a trial going on now that mandates prior treatment, the BYLieve study. That will be helpful but it does not sound like that would really impact your use of the drug too much. Will you now test all of your patients for PI3 kinase mutations?

Cardoso: Not until it is approved. But if approved, that raises the problem of testing, which obviously increases the cost of the treatment because you need to pay for the diagnostic. Overall, it's very interesting because we finally see that if you have an alteration in breast cancer, you can target it with a specific targeted agent and obtain a response. These are paradigms that are very important for us to see proven in our clinical research.

Curigliano: And we have also the chance to use a liquid biopsy, which can assess the mutational status.

Quality-of-Life Data

Rugo: We're going to be talking a lot more about this. I want to close with one brief comment from you, Fatima, about quality-of-life data. We had three presentations in a row at the metastatic proffered paper oral session, two of which were with the CDK 4/6 inhibitor ribociclib, particularly focusing on MONALEESA-7.[5] Could you give us a very brief comment about that?

Cardoso: We had purposely chosen to put quality-of-life issues in the oral session to reinforce how important they are in the management of advanced disease. We also had the opportunity to show the new tool that has been developed by the European Organisation for Research and Treatment of Cancer (EORTC) and which will now be used in all breast cancer trials. The EORTC tool for measuring quality of life in breast cancer has been updated.[6]

Rugo: This is really an exciting thing to add into the global quality-of-life and the functional symptoms scales to focus on breast cancer and to show that these CDK 4/6 inhibitors are well tolerated in premenopausal as well as postmenopausal women.

It's been a very exciting meeting. Fatima, Giuseppe, thank you very much for joining me. It's been a fascinating discussion of these data, and I think we may see drug approvals in the next year or two that change the way we think about breast cancer, and this may bring us further into the world of precision oncology.

Thank you for joining us. I am Hope Rugo speaking from ESMO 2018 in Munich, Germany.


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