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Meisel Reviews Systemic Therapies for Breast Cancer With 2 Case Studies

Tony Berberabe, MPH
Published Online:7:30 PM, Wed July 17, 2019
Jane Lowe Meisel, MD
Jane Lowe Meisel, MD
Jane Lowe Meisel, MD, reviewed systemic therapy options for treating patients with breast cancer with a group of physicians during a Targeted Oncology live case-based peer perspectives discussion. Meisel, an assistant professor in the Department Hematology and Medical Oncology and in the Department of Gynecology & Obstetrics, Emory University School of Medicine, Winship Cancer Institute, explained the treatment considerations she makes for treating patients with breast cancer during the dinner event in terms of 2 case studies.


CASE 1
A postmenopausal 55-year-old African American woman was given a diagnosis of breast cancer 2 years ago, after discovering a lump in her right breast. She was active and had 2 teenage children.

Imaging revealed the likelihood of a multifocal lesion (2.5 cm) in the right breast and right axillary lymph node involvement. Pathology findings from an ultrasound-guided core needle biopsy found histologic grade 3 invasive ductal carcinoma, and her hormone receptor status was assessed as estrogen receptor (ER) negative, progesterone receptor (PR) negative; she was also HER2 negative. BRCA1/2 testing came out negative. 

She underwent mastectomy followed by immediate reconstruction; 2 of 20 nodes were found to be positive. After surgery she was staged as T2pN1M0. 

Following surgery, she received adjuvant doxorubicin/cyclophosphamide followed by paclitaxel (12 weeks); she managed to complete chemotherapy despite significant diarrhea and chemotherapy-induced nausea and vomiting.

In a routine follow-up at 18 months, she reported having worsening cough and abdominal pain. Imaging revealed 3 lesions in her right lung (<2 cm) and several liver lesions, and a biopsy confirmed metastatic triple-negative breast cancer (TNBC).


Targeted Oncology: If this is how she presented before surgery, with staging T2N1, what would you have done?
Meisel:We would probably treat with neoadjuvant therapy. 

Targeted Oncology: When do you give carboplatin in a patient such as this?
Meisel:I think the question of when to administer carboplatin is a tough one. I tend to start with the AC [doxorubicin (Adriamycin) and cyclophosphamide] regimen, giving the patient the expectation that it’s going to be AC-T [AC + paclitaxel (Taxol)]. If the patient doesn’t respond well, we usually bring in the carboplatin with the Taxol. 

If the patient is BRCApositive, I am more likely to add carboplatin than if they aren’t, especially if we find that the patient has a BRCAmutation, because there are some data, particularly in the metastatic setting, [that show] patients respond to carboplatin a lot more vigorously if they have a BRCAmutation than if they do not. So for the rare patient who presents as a neoadjuvant candidate with a BRCAmutation, I would consider using carboplatin. 

For most of us reviewing this case, this appears to be a neoadjuvant patient because we can get a lot of prognostic information from how the patient responds and then have the opportunity to give them more therapy in the adjuvant and neoadjuvant settings. 

Targeted Oncology: Please discuss the phase III IMpassion130 study.
Meisel:This study looked at atezolizumab [Tecentriq] plus Abraxane [nab-paclitaxel] versus placebo plus Abraxane for first-line metastatic TNBC.1Patients were randomized 1:1 into the 2 arms and stratified by prior taxane use, liver metastases (yes vs no), and PD-L1 status on immune cells (ICs; ≥1%] versus negative (<1%).

For baseline characteristics, about 41% of patients were positive on ICs, which is an important prognostic factor. That’s a lot of patients. It was a pretty high-risk population, with 28% having liver metastases, 50% with lung metastases, and 26% having more than 4 sites of metastatic disease.

In the intent-to-treat [ITT] populations, the 1-year progression-free survival [PFS] rates were fairly low in both arms but higher in the atezolizumab arm (24% vs 18%; 95% CI, 0.69-0.92; P= .0025). In the PD-L1–positive population, the 1-year PFS rate was 29% in the treatment arm and 16% in the placebo arm. For the ITT population, the 2-year overall survival [OS] rate was reported at 42% for the atezolizumab plus Abraxane arm and 40% in the placebo plus Abraxane arm. The interim OS analysis in the PD-L1–positive population showed a 54% 2-year OS rate in the atezolizumab arm versus 37% in the placebo arm.

For patients who received atezolizumab, a higher proportion of patients compared with the placebo arm received more Abraxane for ≥6 months (70% vs 59%) and ≥12 months (22% vs 17%). Atezolizumab did not compromise the dose intensity of the Abraxane. The concern is that maybe these patients just needed chemotherapy, but if we give atezolizumab, it might affect how much chemotherapy can be given. This was not the case. If patients are responding better to the combination, maybe they are clinically doing better and feeling better, and as a result, maybe they can tolerate more chemotherapy rather than less. 

For safety, all-cause adverse events [AEs] and treatment-related AEs look stable across both groups. The most common AEs were generally similar between the 2 arms, with the most common grade 3/4 AEs being neutropenia, decreased neutrophil count, peripheral neuropathy, fatigue, and anemia. Grade 3/4 AEs were ≥2% higher in the atezolizumab arm and included peripheral neuropathy (6% vs 3%).  

A higher proportion of the patients in the atezolizumab arm than in the placebo arm reported serious AEs (23% vs 18%), but no serious AEs were reported with a ≥2% difference between the 2 arms. These patients were doing better from a disease standpoint and not suffering much in terms of the AEs. 

There were some AEs suggestive of potential immune-related etiology, with hepatitis and hypothyroidism being the most common, but these are AEs that we look for and are aware of when giving immunotherapy. 


CASE 1 (continued):
Molecular testing was negative for PD-L1 expression. 
The patient was started on treatment with gemcitabine/carboplatin; she required dose reduction for neutropenia; imaging at 3 months showed stable disease.
Seven months after the patient started gemcitabine/carboplatin, imaging showed progression in a single right lung nodule (now 3.2 cm). After a discussion about her therapy choices, the patient opted for treatment with capecitabine.
Imaging at 3 months showed 4 new liver lesions. She started treatment with intravenous (IV) eribulin 1.4 mg/m2on days 1 and 8 of each 21-day cycle. Two weeks after her first dose, she developed grade 3 neutropenia without fever.


Targeted Oncology: What benefit does eribulin offer for this patient after progression on 2 lines of therapy in the metastatic setting?
Meisel:The patient opted for capecitabine. Imaging at 3 months showed 4 new liver lesions. She started treatment with IV eribulin 1.4 mg/m2on days 1 and 8 of each 21-day cycle. [Results from] the EMBRACE trial2showed a 3- to 4-month improvement in OS. [Results from] another study, Study 301,3which looked at patients from first through third lines, showed similar OS. When the EMBRACE data came out, oncologists were excited about eribulin, but when these data came out, the data swung back the other way. 

Based on some real-world data from oncology clinics in the United States,4a study showed that the patients did better in terms of raw survival than reported in EMBRACE and Study 301. It’s definitely an active drug. I don’t use it in first line, but usually I use it in second line and third line. The challenge with many patients with TNBC is that they progress too quickly. You need to move fast with these patients and get them registered, enrolled, and into the protocol.


CASE 2:
A 63-year-old woman was given a diagnosis of T3N1, ER-positive, PR-negative, HER2-negative breast cancer. She received chemotherapy and is now on an aromatase inhibitor (AI).

Thirteen months after starting AI, she presented with asymptomatic metastases to the liver discovered incidentally when CT was done for unrelated abdominal pain.

Staging was otherwise negative for metastases. Her liver function tests were mildly elevated. She had an ECOG performance status of 0. 


Targeted Oncology: Would you repeat molecular testing for this patient?
Meisel:I think we would all agree that, yes, we would repeat molecular testing. We would biopsy the liver and repeat testing. We know that receptors can change some percentage of the time. Also, you want to make sure this is a breast cancer and not something else.

Targeted Oncology: What if the patient has 3 liver metastases and pulmonary nodules as well? How does this affect your treatment plan?
Meisel:If this were the patient, surgery is not an option. She’s had chemotherapy, but we don’t know what specific kind of chemotherapy. She has had progression after 13 months on an AI. She’s ER positive, PR negative, and HER2 negative. Let’s say for the case of argument that she is 70% ER positive. 

At this point, we might want to consider Ibrance [palbociclib] or another CDK4/6 inhibitor plus something else. I also might change the endocrine therapy, but there are a lot of factors that would play into that. There are not a lot of studies whose results show that adding a CDK4/6 inhibitor to an AI after progression has shown benefit.  

Targeted Oncology: Would you consider chemotherapy for this patient?
Meisel:I have had a few cases in which I almost gave a patient with this type of profile “induction” chemotherapy, in someone with ER-positive metastatic disease. One was a young woman who had been on adjuvant tamoxifen for 4 years and presented with a large pleural effusion and liver metastases and was very symptomatic. She had not received AC, so I prescribed AC in the first-line metastatic setting, followed by Ibrance and letrozole.

In another case, I saw a woman who had DCIS [ductal carcinoma in situ] 15 years prior. She presented with a huge pericardial effusion and liver metastases. So she had dramatic presentation for which I felt chemotherapy would benefit. 

In this case, changing the endocrine backbone and adding a CDK4/6 inhibitor would be appropriate. 

Targeted Oncology: If we’re considering fulvestrant (Faslodex) plus a CDK4/6 inhibitor (abemaciclib [Verzenio], palbociclib, or ribociclib [Kisqali]), does the choice of drug affect the outcome?
Meisel:I think palbociclib and ribociclib are closely related, almost “kissing cousins.” The major AE for CDK4/6 inhibitors is neutropenia, particularly with ribociclib and palbociclib. With abemaciclib you see more cases of diarrhea. It’s a little more of a differential effect when comparing CDK4 versus CDK6. So there’s less neutropenia, and it’s dosed continuously as opposed to 3 weeks on and 1 week off.

In the first 2 months, the patient should be checked every 2 weeks with laboratory tests and then after that monthly. And then you can space that out to every 3 months. We’re presenting a poster at ASCO [American Society of Clinical Oncology Annual Meeting] that shows that patients who were not required to come back every 2 weeks for monitoring had no difference in outcomes compared with those who followed the standard monitoring schedule. 


CASE 2 (continued):
The patient received abemaciclib plus letrozole


Targeted Oncology: What steps do you take to mitigate the diarrhea?
Meisel:I don’t start antidiarrheal agents prophylactically. However, if a patient has had trouble with diarrhea when given chemotherapy previously, I do worry about that. Sometimes the pharmacist will call the patient to determine the stool pattern. Sometimes with this drug and niraparib [Zejula], I feel that patient education can be key. So it’s a good way to get the whole team involved. I’ve suggested diet counseling, which I’ve done a handful of times, to get the nutritionist on board and educating the patient. The diarrhea is easier for patients to recognize than neutropenia.  

I have also prescribed a good amount of palbociclib. We’ve done a lot of clinical studies using the drug, and I feel that I know it well. I have not used ribociclib at all. I think with abemaciclib, you can dose-reduce, and I’ve dose-reduced because of the diarrhea, and patients had great outcomes with that. So [the diarrhea] is not as insurmountable as it seems.

For the first-line trials of the CDK4/6 inhibitors—PALOMA-2, MONALEESA-2, MONARCH 3—the outcomes were pretty similar, and overall response rates were higher when the CDK4/6 inhibitor was included with the endocrine therapy, the clinical benefit rate was higher with the CDK4/6 inhibitor, and PFS was markedly improved.5-8

To me, there is still some argument whether OS is relevant, and we’re still looking at those data, but for these ER-positive patients in the first-line setting, we’re going to get so many more lines of treatment that PFS is going to be more relevant, and it’s such a major improvement in the real world. If you can say to the patient that you can stay on this drug for 2 years before I have to give you bad news, rather than after 1 year, you’re doing your patients a real favor.

Targeted Oncology: What are the AEs and the dosing associated with each CDK4/6 inhibitor?
Meisel:For abemaciclib, which is also approved as a monotherapy for ER-positive metastatic breast cancer, 200 mg twice daily is the monotherapy dose, whereas the dose is 150 mg when given with an endocrine partner. The major toxicities are cytopenias for palbociclib and ribociclib and more cases of diarrhea and fatigue for abemaciclib. 

The subgroup analyses for PALOMA-2 and MONALEESA-2 mainly show that patient age was not a factor. It didn’t matter whether your metastases were visceral or nonvisceral, and it didn’t matter whether your endocrine therapy was an AI or something else or whether you had hormonal therapy. For performance status, which for most patients was 0 or 1, it didn’t matter whether you were doing well or slightly well; everyone essentially benefited from the combination. So all these important subgroups got benefit from adding a CDK4/6 inhibitor. 

When looking at patients with lung and liver involvement, in our more high-risk, ER-positive patients, we see a significant benefit to adding palbociclib with the endocrine therapy. In some patients who had lung involvement, we see a PFS of 22 months versus 14 months. For liver involvement, which I feel is the most difficult, with the highest risk to manage, patients who received palbociclib and letrozole had a PFS of nearly 14 months versus 8 months in patients who only received letrozole. 

PALOMA-3, which looks at fulvestrant plus palbociclib, is a second-line study that looks at patients who progressed on adjuvant endocrine therapy or who progressed within 12 months of stopping endocrine therapy. The OS in the ITT arm demonstrated a benefit in the fulvestrant plus palbociclib arm of 34.9 months versus 28.0 months. This was a 54-month cutoff, which isn’t statistically significant yet, but I think we will eventually see that there’s a benefit to seeing how long people live if we use these treatments sooner. Long-term responses (>18 months) to the fulvestrant plus palbociclib combination were more likely to occur in patients who had 1 site of metastatic breast cancer, were less heavily pretreated, and had PR-positive disease. This just speaks to the fact that if you are more endocrine sensitive, you are going to do better with this combination.

A subgroup analysis of MONARCH 3 showed that everyone benefits no matter which subgroup you are in. For the most part, every subgroup benefited from adding the abemaciclib. For prognostic subgroups in MONARCH 2 and 3, the patients who received the greatest benefit in objective response rate were PR negative, had liver metastases, and had high-grade disease. 

In our original case, the patient progressed after 13 months on an AI, so adding abemaciclib and fulvestrant makes sense.

Targeted Oncology: What if progression occurred 5 years after completion of adjuvant therapy?
Meisel:An option would be to go with Faslodex rather than add a CDK4/6 inhibitor. The biology is different in slow-progressing disease. Switching to a different AI would be an option to consider. There are also studies that are looking at Faslodex in the second line coupled with other therapies. Other studies are also exploring immunotherapy and CDK4/6 inhibitors, which I am excited about because we’re about to open one. 

There are data in patients who present as metastatic in the first-line setting. In particular, [results from] the FALCON study showed fulvestrant was effective as monotherapy, but for patients, it might be hard to come into the clinic for an injection versus just taking a pill.

I also have patients who started their AI in 1995, completed treatment 5 years later, and came back to see me with limited bone disease. Those are patients in whom I’ll start an AI and I see in 3 months. These patients have such indolent disease, especially if they’re older, that you can avoid giving them agents that cause neutropenia or diarrhea. 

Targeted Oncology: How does tumor grade affect your treatment decision?
Meisel:Other factors might affect treatment decisions and how people respond. Patients with higher-grade tumors benefited more from CDK4/6 inhibitors. PFS was 14.4 months in MONARCH 2,9which looked at abemaciclib versus fulvestrant alone—14.4 months for the treatment arm versus 5.72 months for the fulvestrant arm. 
 
 
References:
  1. Schmid P, Adams S, Rugo HS, et al. IMpassion130: results from a global, randomised, double-blind, phase III study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naïve, locally advanced or metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2018;29(suppl 8; abstr LBA1_PR). doi: 10.1093/annonc/mdy424.008.
  2. Cortes J, O’Shaughnessy J, Loesch D, et al; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-923. doi: 10.1016/S0140-6736(11)60070-6.
  3. Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015;33(6):594-601. doi: 10.1200/JCO.20152.4892.
  4. Mougalian SS, Copher R, Kish JK, et al. Clinical benefit of treatment with eribulin mesylate for metastatic triple-negative breast cancer: long-term outcomes of patients treated in the US community oncology setting. Cancer Med. 2018;7(9):4371-4378. doi: 10.1002/cam1705.
  5. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.
  6. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547. doi: 10.1093/annonc/mdy155.
  7. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer [erratum in N Engl J Med. 2018;379(26):2582. doi: 10.1056/NEJMx180043]. N Engl J Med.2016;375(18):1738-1748. doi: 10.1056/NEJMoa1609709.
  8. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646. doi: 10.1200/JCO.2017.75.6155.
  9. O’Shaughnessy J, Goetz MP, Sledge GW, et al. The benefit of abemaciclib in prognostic subgroups: an update to the pooled analysis of MONARCH 2 and 3. Cancer Res.2018;78(suppl 13; abstr CT099). doi: 10.1158/1538-7445.AM2018-CT09


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