July 2020 Edition Vol.11, Issue 7

A Breast Cancer Roundtable: CDK4/6 Inhibition, HER2-Positive Disease, and the Role of Immunotherapy

A panel of experts at the 2020 ASCO annual meeting discussed treatment advances and setbacks of key data published in the area of CDK4/6 inhibition, HER2-positive disease, and immunotherapy in breast cancer.

The panel, led by Dean Gesme, MD, Medical Oncologist in Minneapolis, Minnesota, included Debra Patt, MD, MPH, MBA, Vice President, Medical Oncologist/Hematologist, Texas Oncology, Joyce O’Shaughnessy, MD, Director of Breast Cancer Research at Baylor-Simmons Cancer Center and The US Oncology Network, and Sara Tolaney, MD, MPH, Assistant Professor of Medicine, Harvard Medical School and Medical Oncologist at Dana-Farber Cancer Institute.

Following are highlights from the expert panel discussion.

CDK4/6 Inhibition: Metastatic vs. Adjuvant Setting

Dr. Patt: As an oncologist practicing for 14 years, CDK4/6 inhibition has probably been one of the most meaningful changes in breast cancer, helping patients live longer with metastatic disease and with great quality of life. We have seen progression-free survival (PFS) dramatically improve, and in this last year, we’ve even seen changes in overall survival (OS). At ESMO, MONARCH 2 reported an OS advantage utilizing abemaciclib,1 and at ASCO, we saw data from MONALEESA-7 demonstrate an OS benefit with ribociclib.2

We have not yet seen palbociclib report an OS benefit, but there was a meta-analysis of CDK4/6 inhibitors that showed an OS benefit,3 and there is real-world evidence of palbociclib use from the Flatiron Database that demonstrates an OS benefit as well.

However, I was disappointed by the results of the PALLAS trial that showed no benefit from the adjuvant use of palbociclib. As breast cancer specialists, when we see drugs that are very effective in the metastatic setting, we want to bring them to the adjuvant setting to see patients benefit and increase the likelihood of cures. But, the preliminary results of adding CDK4/6 inhibition to the adjuvant setting have not been optimistic.

Dr. O’Shaughnessy: Although we haven’t seen the PALLAS data yet, it was surprising to hear that the statistical endpoints had not been reached. It’s rare to see agents that have a substantial impact on the natural history of metastatic breast cancer not translate into improvement in outcome in early-stage disease, but we will have to wait until later this year to see the actual data.

It was exciting to hear that MonarchE, which evaluated a higher-risk population of patients, is a positive trial. Abemaciclib is a different agent than palbociclib, so there may be some differences that play out in the adjuvant setting, but it may be patient population more than anything. There may be a need to enrich for not only high-risk patients, but those specifically at high risk to recur within the first five years. However, there’s no doubt that these agents have transformed our patients lives in the metastatic setting, and the increasing survival data emerging are extremely encouraging.

Dr. Tolaney: I was also stunned by the press release from PALLAS given the fairly tremendous benefit that we see in the metastatic setting. It’s possible that senescence in an early-stage setting isn’t adequate to have an impact on rates of occurrence in an adjuvant setting. There could be something about the mechanisms of causing cellular senescence that impact this as suggested by the FELINE study, which showed no difference in PEPI 0 rates with letrozole versus letrozole and ribociclib.4 PALLAS also included stage IIA patients who do very well with endocrine therapy alone, so it might not be the optimal patient population for CDK4/6 inhibitors.

It is great to hear about the benefit in the MonarchE study, but we won’t know if it’s because of the different CDK4/6 inhibitor used or the higher-risk population. When we have the data from the PALLAS study, it will also be interesting to see whether certain subgroups derived benefit from palbociclib. Data from PENELOPE-B, which enriched for a high-risk population but only gave one year of palbociclib, and NATALEE, which looked at three years of adjuvant ribociclib, may help answer questions about CDK4/6 inhibitors in the early-disease setting.

CDK4/6 Inhibition: Management of Toxicities

Dr. O’Shaughnessy: The combination of endocrine therapy with CDK4/6 inhibition leads to excellent results in the majority of our patients, and all three CDK4/6 agents do well in this regard. I tend to go for the least toxic of the treatments, which I think are palbociclib and ribociclib, to avoid GI toxicity. It’s only a small minority of my patients who can’t take abemaciclib because of diarrhea, but they are there, and they can’t tolerate it.

Conversely, when it’s highly unlikely a patient is going to benefit from endocrine therapy alone due to heavy disease burden and aggressive disease with and clonal heterogeneity, I tend to reach for abemaciclib because I think it’s a broader spectrum agent. Plus, you don’t have to take the week off, which may be useful in controlling rapidly progressing disease.

Dr. Patt: From a toxicity standpoint, I also favor ribociclib and palbociclib, but I may feel compelled to put patients on abemaciclib (for the broader mechanism of action). If patients do really well with that, I often end up switching them a year or two later because of toxicity, and they are usually grateful.

Dr. Tolaney: I consider patient factors when trying to choose the agent. If someone has a lot of marrow involvement with their cancer and low counts at baseline, I tend to go with abemaciclib, but if a patient has irritable bowel syndrome and has issues with diarrhea at baseline, I’ll use palbociclib or ribociclib.

There are also some data to suggest that abemaciclib has CNS penetration and CNS activity, so I may preferentially choose abemaciclib in patients with brain metastases. In addition, subgroup analyses have suggested that patients with clinically concerning characteristics such as significant visceral involvement have larger benefits from abemaciclib relative to no abemaciclib. I keep those factors in mind when trying to choose between the agents.

Treatment of HER2-Positive Advanced Breast Cancer

Dr. O’Shaughnessy: There are a lot of new agents that are changing our practice. Data from the APHINITY trial, presented at San Antonio last year with six-year median follow-up, continued to show superior invasive disease-free survival (iDFS) in the adjuvant setting with the addition of pertuzumab to trastuzumab and chemotherapy, even in patients with a path CR (pathologic complete response) who receive TCHP (Taxotere + Carboplatin + Herceptin + Perjeta).5

When somebody achieves a path CR, my own feeling is that we should give one year of pertuzumab so that patients receive the full benefit. If you start with it in a neoadjuvant setting, you should finish it. Now, in APHINITY, it was only the node-positive patients who benefited – there was no benefit in the node negative – but in the neoadjuvant setting we never quite know for sure who is node negative. What was also nice about APHINITY was that patients had the same benefits with the addition of pertuzumab regardless of whether they were ER positive or negative. So, we have very good evidence that pertuzumab improves iDFS outcomes in the higher-risk population.

For patients who do not have a path CR, compelling data from the KATHERINE study showed 11% absolute improvement in iDFS at three years follow-up with T-DM1 for 14 cycles. At ASCO, a presentation of the KATHERINE biomarker data showed that T-DM1 worked in every single subset, including patients with or without PIK3CA mutation or PD-L1 expression.6 In addition, patients benefited from T-DM1 regardless of the level of HER2 expression, which was something that has been debated at our tumor board.

Patients who do not have a path CR and still have considerable residual disease are going to receive T-DM1, which will improve their median iDFS, but if they are ER positive, neratinib can be very beneficial. Data from the ExteNET study showed that patients without a path CR who went on to receive neratinib had a 7% to 8% improvement in iDFS at five-years follow-up.7 That’s big. Even though patients get fatigued with all this treatment, if they are high-risk individuals who have a lot of residual disease or started off with a lot of disease, I’m a big believer in neratinib.

In the metastatic setting, first-line treatment is still the CLEOPATRA regimen (taxane or vinorelbine plus trastuzumab and pertuzumab), which showed a big survival advantage in a trastuzumab-naïve population (only 11% had prior trastuzumab in the adjuvant setting).8

In the second-line setting, however, treatment is evolving. A new agent, tucatinib, a very pure TKI that inhibits only HER2 and does not have off-target effects on HER1, demonstrated striking activity in the brain in combination with capecitabine and trastuzumab in the HER2CLIMB trial.9 Data presented at San Antonio showed both PFS and OS advantage in the overall treated population with capecitabine and trastuzumab plus tucatinib versus placebo. Data presented at ASCO, specifically in patients with brain metastasis, showed survival improvement in those with active as well as stable brain metastasis. The active brain metastasis actually had a more compelling improvement in survival, but they were both positive for OS. Clearly, if our patients have brain metastases and they progress on the CLEOPATRA regimen, tucatinib would be an excellent choice, and it has now been approved in the second-line or greater setting.

Trastuzumab deruxtecan (T-DXd) was also recently approved by the FDA. It’s an antibody drug conjugate that’s extremely powerful. In a very late-line population, the single arm DESTINY-Breast01 study showed a response rate of 60% and virtually every patient had clinical benefit.10 Unfortunately, there were a few deaths among the 13% of patients who had interstitial lung disease, but the PFS and OS looked very strong.

So, clinicians have a menu of choices following CLEOPATRA. Neratinib plus capecitabine was also approved in the third-line or greater metastatic setting, which could be an option for patients with brain metastasis.

Dr. Patt: In our HER2-positive patients, we have achieved such great disease control systemically, but the disease in the brain can be our mountain to climb, and sometimes it’s Everest. So, I really like the HER2CLIMB data of tucatinib. In patients with brain metastasis who received tucatinib in addition to capecitabine and trastuzumab, the CNS- free progression was 9.9 months in comparison to 4.2 months in the control arm, and there was a 42% reduction in deaths. To me, tucatinib is a really meaningful tool for brain metastasis.

Neratinib also has activity in the brain, and it’s meaningful for high-risk patients too. I wasn’t an early fan of neratinib because I feel like it’s so toxic, but with immediate use of anti-diarrheal agents, they’ve been able to mitigate a lot of the toxicity with neratinib.

T-DXd has also been a really meaningful addition, and there’s activity in the brain. Of the 24 patients with CNS metastasis, 58% had confirmed objective response, and 4% actually had a complete response.

In my mind, these three trials have been the most meaningful to our HER2-amplified patients. While I want to see progress in every front against the disease, it’s the brain metastases that keep me up at night. I’m excited that I have more to bring to the table in that patient population.

Dr. O’Shaughnessy: I totally agree. Although T-DM1 made a major impact in reducing the risk of recurrence and death in patients with residual disease, it was disappointing in the KATHERINE trial that there was no impact on the development of brain metastases. Half of the recurrences following treatment in that trial were in the brain, so it’s not a small problem whatsoever. Hopefully, we’ll get tucatinib pretty quickly into the curative setting.

Dr. Tolaney: Obviously, I’ve been very impressed with both the HER2CLIMB data and the data we saw from DESTINY-01 looking at T-DXd. The challenge that we have for T-DXd is that the data are honestly unprecedented. We don’t see agents that have a 16-month PFS in a population with a median of six prior lines of therapy for metastatic disease. That’s virtually unheard of. On the other hand, it’s a single arm study; we don’t have randomized data or survival data yet. There is also concern for toxicity with interstitial lung disease. I’d like to see the randomized data to feel a little more comfortable with the toxicity profile, but I’m very encouraged by the data, and my hope is that we’re also likely to see efficacy in the brain.

In the third-line setting, we’re going to be choosing between the HER2CLIMB regimen and T-DXd, and I think it will depend on the patient. If a patient has active brain mets, the HER2CLIMB regimen is very attractive, and it’s what I would likely choose given the robust survival benefit. Where the tossup comes is the population of patients with stable treated brain mets. In DESTINY-01, T-DXd had an 18-month PFS in that subgroup. It’s a small study and not randomized, but that’s a really impressive PFS. I think you could go either way. If someone has no issues with underlying pneumonitis and no significant pulmonary disease, T-DXd would be a reasonable option as would the HER2CLIMB regimen. Randomized data with T-DXd will help us better solidify those decisions.

Immunotherapy in Breast Cancer

Dr. Tolaney: Immunotherapy has had tremendous advantage in many diseases, but breast cancer has taken longer to see benefits. Although we were initially disappointed by the activity of single-agent checkpoint inhibitors, there has since been a lot of interest in augmenting the immune response with the combination of immunotherapy and chemotherapy. That led to IMpassion130, a phase III study that randomized first-line triple-negative patients to receive nab-paclitaxel with or without atezolizumab. Data showed an improvement in PFS of approximately two and a half months in patients with PD-L1 positive metastatic triple-negative breast cancer.11 While the OS was not technically statistically significant given the hierarchical design of the trial, there was a seven-month difference favoring atezolizumab. Those data were encouraging and led to the FDA approval of the combination of nab-paclitaxel and atezolizumab in patients with PD-L1 positive triple-negative disease.

At ASCO, data from Keynote-355 showed a significant improvement in PFS for patients who were PD-L1 positive, but the benefit was seen only in those with a combined positive score (CPS) of 10 or greater.12  (Unlike Impassion130, Keynote-355 enrolled patients who relapsed as early as six months after chemotherapy and allowed choice of chemotherapy backbone.) While there was a numerically greater PFS in the CPS 1 and higher group from about 5.6 to 7.6 months, this was not statistically significant. OS data was not presented at ASCO.

These data are exciting and hopefully will lead to approval of pembrolizumab for metastatic triple-negative patients with a CPS of 10 or higher, but I think it leaves us with some challenges about how best to test for PD-L1, which checkpoint inhibitor to use, and what to do with early relapsers.

Another exciting area of interest for immunotherapy is in the early-disease setting. Many of us think that immunotherapy may work even better in patients who are not pretreated because we know that the immune microenvironment is much richer in early tumors, which have more tumor infiltrating lymphocytes and PD-L1 expression. At ESMO and San Antonio, data from KEYNOTE-522, which looked at adding pembrolizumab to chemotherapy (carboplatin with paclitaxel followed by anthracycline and cyclophosphamide), showed approximately 14% improvement in path CR.13 Interestingly, the benefit was not restricted to PD-L1-positive patients and was, in fact, numerically greater in the PD-L1-negative group, suggesting benefit regardless of PD-L1 status. However, longer follow-up is needed to see if a trend towards improved event-free survival becomes statistically significant.

Conversely, data from the NeoTRIP trial, which looked at the addition of preoperative atezolizumab to a non-anthracycline backbone of carboplatin and taxane, did not show improvement in path CR in either PD-L1-positive or PD-L1-negative groups. We’re not sure if this negative result is due to the lack of anthracycline. There is some suggestion that anthracycline may be more synergistic with checkpoint inhibition. It could also be due to differences between PD-L1 and PD-1 inhibition or differences in the patient populations.

A lot of questions remain, but it’s exciting that we’re now seeing benefits for both atezolizumab and pembrolizumab in the metastatic setting, and in the early-disease setting, a path CR benefit from the addition of pembrolizumab to chemotherapy. Hopefully, with longer follow-up, we’ll see benefit with event-free survival as well.

Dr. O’Shaughnessy: With KEYNOTE-355, it’s very good to see another data set that puts checkpoint inhibitors in the first-line metastatic triple-negative population. Interestingly, 38% of the patients were CPS 10% or more with the 22C3 antibody, and 40% to 41% of the patients in IMpassion130 were PD-L1 positive with the SP142 assay. We don’t know that they’re exactly the same patients, but it seems that about 40% of our patients may really benefit from a checkpoint inhibitor.

In KEYNOTE-355, approximately 25% of patients have a PFS of at least two years with the chemotherapy plus pembrolizumab combination, so I think this cements the approach for us. Once it’s FDA approved, it will give us another option besides taxane for our PD-L1-positive patients.

Dr. Patt: I’m so excited about immunotherapy in all cancers and especially in breast cancer, but in my mind, there’s uncertainty at this point that we’re using the right criteria to understand which patients might benefit or even if we’re looking in the right way to see who might benefit. I had a patient on the KEYNOTE-522 trial who had an early relapse but later responded and now has been on immunotherapy for a couple of years. Are we having enough patience to understand that it might take longer to have a response but those responses might be more durable? There are many questions. What I don’t have a question about is the benefit in early-stage disease. Having accrued a number of patients on the KEYNOTE-522 trial, I would love to see that [regimen] approved so that we can improve the likelihood of path CR for our triple-negative patient population. And we’re currently asking the question for our ER-positive patients. So, I’m very excited about immunotherapy, but I think that there are still a lot of unknowns about how we optimally use it, and even how we evaluate for response.


References

  1. Sledge Jr. GW, Toi Masakazu, Neven P, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol . 2019 Sep 29;6(1):116-124.
  2. Im SA, Lu YS, Bardia A, et al. Overall Survival With Ribociclib Plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316.
  3. Schettini F, Giudici F, Giuliano M, et al. Overall Survival of CDK4/6-inhibitors-based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis. J Natl Cancer Inst . 2020 May 14;djaa071.
  4. Khan QJ, O’Dea A, Bardia A, et al. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 505-505.
  5. Piccart M, Procter M, Fumagalli D, et al: Interim overall survival analysis of APHINITY (BIG 4-11): A randomized, multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab vs chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-04. Presented December 11, 2019.
  6. Denkert C, Lambertini C, Fasching PA, et al. Biomarker data from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer. Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 502-502.
  7. Chia SK, Martin M, Holmes FA, et al. PIK3CA Alterations and Benefit With Neratinib: Analysis From the Randomized, Double-Blind, Placebo-Controlled, Phase III ExteNET Trial. Breast Cancer Res . 2019 Mar 11;21(1):39.
  8. Swain SM, Baselga José, Kim SB, et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-positive Metastatic Breast Cancer. N Engl J Med. 2015 Feb 19;372(8):724-34.
  9. Lin NU, Murthy RK, Anders CK, et al: Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). ASCO20 Virtual Scientific Program. Abstract 1005. Presented May 29, 2020.
  10. Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 2020; 382:610-621.
  11. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 2018;379:2108-21.
  12. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 1000-1000.
  13. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 2020; 382:810-821.

 

 

 

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