My Notes from SABCS 2017

The San Antonio Breast Cancer Symposium (SABCS) is an annual event providing state-of-the-art information about breast cancer and its treatments to an international audience consisting of researchers, physicians, patients, and advocates.I would like to thank the Metastatic Breast Cancer Alliance (MBCA) for sponsoring my attendance, and for their continued commitment to improving the lives of those with metastatic breast cancer.

Below are key points that I gleaned at the 2017 SABCS conference, albeit that there were some intriguing sessions that I was unable to attend (such as the presentation about Lobular Breast Cancer).After returning home, I reviewed and cross-checked my notes with online articles and have provided links for ease of reference. Also, please note that the information herein has been incorporated into my complimentary book entitled, "The Insider's Guide to Metastatic Breast Cancer," which can be requested via email to bestbird@hotmail.com

It was encouraging to observe numerous initiatives underway regarding immunotherapies, and to see that many drugs that are already approved or studied for one mbc subtype are being tested on other subtypes.Also exciting was hearing the FDA's perspective about reducing drug dosages in view of toxicities, the FDA's willingness to review and - as applicable - approve biosimilar drugs, and their desire to learn more about Patient Reported Outcomes regarding clinical trials.Finally, I was grateful for the opportunity to participate in a discussion with Dr. Nick Wagle and Dr. Corrie Painter of the MBC Project that is enrolling and studying mbc patients nationwide to determine key factors regarding treatment response, resistance, and outcomes.All mbc patients are welcome to participate in this groundbreaking study: https://www.mbcproject.org/

1. FDA Updates:

a. Reducing the Maximum Tolerated Dose Due to Drug Toxicities:

Dr. Tatiana Prowell of the FDA strongly stated that patients do not have to use the FDA-approved dose of a drug if there is reason for using a lower, less toxic dose.She specifically stated, "Dose is something that we are increasingly recognizing as a common error that is probably the easiest to avoid. In oncology, specifically, drug developers have a tendency to move forward with the maximum tolerated dose, even though it is not clear it is necessary or appropriate for targeted drugs. This happens even when they have data suggesting that a targeted therapy maximally inhibits or stimulates its target at a much lower dose. It results in a lot of unnecessary toxicity." From:http://cdn2.hubspot.net/hub/1670/file-983271054-pdf/Tatiana_Prowell_(1).pdf?t=1449608504236

Data supporting the equal (and in some cases, superior) efficacy of reduced doses is becoming available as per the following Poster:

b. Clinical Trial Endpoints: Dr. Prowell indicated that Patient Reported Outcomes should demand as much attention as other clinical trial endpoints, and that they can serve as a basis for selection or dismissal of drugs.

c. New Working Group: The FDA and the Clinical Trials Transformation Initiative (CTTI) will be working together to create a new work group with patient advocacy organizations to talk about patient engagement at the FDA.This initiative is part of the FDA's commitment to raising greater patient involvement in the FDA's decision making process. The new work group will create a forum to exchange information, ideas, and experiences relative to matters of interest to patients and patient advocates, and has established this new website regarding their endeavors: htps://www.fda.gov/ForPatients/PatientEngagement/ucm506248.htm

d. Herceptin Biosimilar drug Approval: On Dec. 1, 2017, the FDA approved Ogivri (Trastuzumab-Dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer whose tumors overexpress the HER2 gene (HER2+). Ogivri is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second biosimilar approved in the U.S. for the treatment of cancer.From: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm587378.htm

2. Biomarkers and Tumor Mutations:

a. Biomarkers:It was noted that in clinical trials that leverage or study biomarkers, a common problem is that the cutoff for positivity for the specific biomarker is not clearly defined, and hence future studies should endeavor to quantify cutoff points where feasible Furthermore, it is important that these studies include a group of patients without the biomarker as well as a group of patients with the biomarker for comparison.

b. ESR1 Mutations and Response to Future Treatment: It was found that ESR1 mutations found in tumors are not necessarily always predictive of response to future treatment.For example, in an analysis of women who had experienced progression on prior endocrine therapy and were treated on the randomized PALOMA-3 trial with fulvestrant (Faslodex) plus either Ibrance or placebo, the addition of Ibrance reduced the risk of progression-free survival similarly (by about 50%) regardless of the presence of ESR1 mutations. This is significant because ESR1 mutations typically indicate acquired resistance to hormonal therapy. From: http://www.mdedge.com/oncologypractice/article/111684/breast-cancer/esr1-mutations-found-prognostic-not-predictive

c. Tumor Mutations and Exceptional (unusually long) Survival: In an initial study of "Outliers" (breast cancer patients who have lived an unusually long time with the disease), it was determined that in hormone receptor positive patients, there were no differences in genetic mutations between patients who lived unusually long vs. those who did not. Conversely, in the hormone receptor negative population, longer-lived patients tended to have increased mutations in the PI3K pathway and invasion pathways. T-cell infiltrates did not correlate with longevity in either group, with the possible exception of CD-4 activated T-cell infiltrates.

"Outlier" Criteria for this study: "Exceptional Survivors with hormone receptor positive disease" were defined as patients living 10 years or more after their initial (either early stage breast cancer or de novo Stage IV) diagnosis, and "Exceptional Survivors with hormone receptor negative disease" were defined as those living 5 years or more after their (early stage breast cancer or de novo Stage IV) diagnosis.Dr. Mark Burkard of the University of Wisconsin–Madison is hoping to continue studying Exceptional Survivors living with mbc, and the new study is currently undergoing the IRB process.

3. Therapeutic Strategies for Triple Positive MBC (MBC that is ER Positive, PR Positive, and HER2 Positive):

The following open-ended guidelines for Triple Positive MBC therapies are continually being reassessed, and the information below has been combined from SABCS 2017 and other sources:

• First-line therapy for triple positive patients remains controversial.According to information delivered at 2017 SABCS, first line therapy should consist of Herceptin, Perjeta, and hormonal therapy.Other sources indicate that it might consist of a combination of Herceptin, Perjeta, and chemotherapy.(Yet another source indicates that the degree of hormonal expression may help to predict treatment outcomes: according to a 2017 Cure Today magazine article, triple positive mbc patients with Estrogen Receptor (ER) expression in more than 30% of cancer cells significantly predicted a lower probability of response to chemotherapy plus Herceptin).

Another source indicated that for select patients, such as those with contraindications and/or slow growing mbc, hormonal therapy administered with either Herceptin or Tykerb (Lapatinib) may be substituted for a chemotherapy-based HER2-targeted regimen because it may have fewer side effects.

• Second-line therapy should be Kadcyla (TDM-1), and all sources appear to agree on this.
• Third-line therapy and beyond may vary.Treatment depends upon what therapies the patient received as the first- and second-line treatments. Options include Kadcyla (TDM1), hormonal therapy or chemotherapy with Herceptin (and in some cases with Tykerb), the combination of Herceptin and Tykerb, or a Perjeta-based regimen if the patient had not previously received Perjeta.

4. A Quick Note About Immunotherapy: As per medical oncologist Dr. Hope Rugo, immunotherapy tends to work more effectively in less heavily pre-treated patients.

5. Clinical Trials:

New Discoveries Regarding Potential Therapeutic Targets: There is encouraging news in that additional breast cancer cell receptors and growth factors are continually being discovered across all mbc subtypes, such as Androgen and FGFR1 (the latter of which may signify resistance to hormonal therapy). There is also a relatively new target of the zinc transporter "LIV-1" (SLC39A6), which is expressed in most mbc patients, including TNBC.

As of Dec. 2017, drugs targeting AR, FGFR1, and LIV1 are being tested in clinical trials.

a. Clinical Trials for Hormone Receptor Positive, HER2 Negative Premenopausal Patients:

i. Kisqali (Ribociclib) in Premenopausal Women: Kisqali has not yet been approved for premenopausal, hormone receptor positive, HER2 negative mbc patients and is being studied in this population.A Phase III randomized, double-blind, placebo-controlled trial called MONALEESA-7 evaluated the efficacy and safety a non-steroidal aromatase inhibitor (or Tamoxifen) plus Goserelin ("Zoladex," which decreases estradiol production) vs. a combination of Kisqali plus a non-steroidal aromatase inhibitor (or Tamoxifen) plus Goserelin.

Patients taking Kisqali in combination with an aromatase inhibitor (or Tamoxifen) plus Goserelin demonstrated a median Progression Free Survival (PFS) of 23.8 months vs. 13.0 months for patients in the aromatase inhibitor (or Tamoxifen) plus Goserelin group.Furthermore, patients in the Kisqali arm demonstrated a clinically meaningful improvement in pain as early as eight weeks of the trial, and they were able to sustain and maintain their health-related quality of life (QOL) for a longer than the other patients.From: https://www.streetinsider.com/Corporate+News/Novartis+AG+(NVS)+Announces+Data+from+Phase+III+MONALEESA-7+Trial+Showing+Superior+Median+PFS+Compared+to+Oral+Endocrine+Therapy+as+First-Line+Treatment/13575487.html

Kisqali Warning:It should be noted that Kisqali is accompanied by warnings and precautions about QT interval prolongation - which can lead to a type of cardiac arrhythmia that is a risk factor for death – as well as hepatobiliary toxicity (having to do with the liver plus the gallbladder, bile ducts, or bile).From: http://www.medscape.com/viewarticle/877177

ii. Kisqali in Combination with Afinitor and Aromasin: Kisqali is currently being studied in combination with Afinitor and Aromasin for hormone receptor positive, HER2 negative mbc patients whose disease progressed on a prior CDK4/6 inhibitor therapy, Faslodex, an aromatase inhibitor, or Tamoxifen. A Clinical Benefit Rate (CBR) of 50% was seen at 6 months in patients who had previously experienced disease progression on a CDK4/6 inhibitor.The combination appears to be well-tolerated thus far, with no new safety issues observed.

iii. Verzenio (Abemaciclib) and Keytruda (Pembrolizumab): The combination of Verzenio and Keytruda showed preliminary signs of activity without additional toxicity in 28 HR+, HER2- patients who had ≥3 sites of metastatic disease and who had received a median of 3 prior therapies for mbc.At the 4-month analysis, the objective response rate (ORR) with the combination was 14.3%, which was less than the 19.7% response rate seen with single-agent Verzenio in the MONARCH-1 trial.That said, the trial investigators noted that the median time to response for Verzenio has historically been 3.7 months, suggesting the efficacy is likely to improve with longer follow-up.The rationale for combining Verzenio with Pembrolizumab came from preclinical data showing that Verzenio may induce intra-tumor immune inflammation with synergy, and enhanced efficacy, when combined with PD-L1 blockade in the setting of anti–PD-L1 refractory disease.From: http://www.onclive.com/web-exclusives/abemaciclib-pembrolizumab-shows-early-promise-for-hrher2-breast-cancer

iv. Arimidex and Faslodex: A study reported that for hormone receptor positive, HER2 negative MBC patients in the combination arm, there was a median Overall Survival (OS) of 49.8 months, which is the longest ever reported for this type of patient.The combination appeared to be of special benefit to patients with no prior endocrine therapy, and/or who recurred after 10 years following a diagnosis of early stage disease.(As of Dec. 2017, I was unable to find a recruiting study for this combination).

b. Clinical Trials for HER2 Positive Patients:

Keytruda (Pembrolizumab) plus Herceptin: For patients with HER2 positive, PDL-1 positive MBC that was resistant to Herceptin or to TDM-1 treatment, the results of the PANACEA clinical trial may be intriguing.This trial indicated that the combination of Keytruda and Herceptin reached an objective response rate (ORR) of 15.2% in patients with trastuzumab or TDM-1 resistant, PD-L1–positive, HER2-positive mbc with an average disease control duration of 11.1 months.Higher levels of sTILs (stromal Tumor Infiltrating Lymphocytes) were associated with improved response and disease control in the PDL-1 positive group. Among PD-L1+ patients with sTILs ≥5%, the disease control rate was 47% versus 5% in patients with sTILs <5%.Notably, patients with PDL-1 negative disease did not respond whatsoever to this treatment.(As of Dec. 2017, there is at least one recruiting clinical trial testing Keytruda in HER2 positive mbc patients). As an aside, Keytruda has already been FDA-approved for patients with metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

Note: Clinical trials are underway to test CDK4/6 inhibitors, in conjunction with other drugs, in HER2 positive patients.

c. Clinical Trials for TNBC MBC Patients:

i. IMMU-132:IMMU-132 ("Sacituzumab Govitecan") is an SN-38 Antibody-Drug Conjugate (ADC) that targets a special antigen called "TROP-2" expressed on many cancers. (ADCs are an emerging novel class of anticancer treatment agents that combines the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs). A blinded, independent review by a team of radiologists observed an Overall Response Rate (ORR) of 31%, including six Complete Responses (CRs) and 28 Partial Responses (PRs) in 110 patients with TNBC mbc after receiving IMMU-132.The median duration of response was 9.1 months.Notably, 9 responders were progression-free for more than one year from the start of treatment, 4 of which were progression-free for more than two years. As of the June 30, 2017 data cutoff, 12 responding patients were still receiving the drug.Overall, patients benefited from IMMU-132 treatment irrespective of age, onset of metastatic disease, or number of prior regimens.

Based upon this and other studies, this drug has received FDA "Breakthrough Therapy" Designation (this is a form of Fast Track Designation, which is meant to facilitate the development and review of new drugs intended to treat serious conditions).As of Dec. 2017, IMMU-132 is being studied in clinical trials. From: https://globenewswire.com/news-release/2017/12/06/1234225/0/en/Immunomedics-Announces-Updated-Results-With-Sacituzumab-Govitecan-IMMU-132-In-Patients-With-Relapsed-Or-Refractory-Metastatic-Triple-Negative-Breast-Cancer-mTNBC.html

ii. SGN-LIV1A: The "LIV-1" protein is expressed by most metastatic breast cancers, including TNBC.SGN–LIV1A, an Antibody Drug Conjugate (ADC), is an experimental drug that targets the zinc transporter LIV-1 for the treatment of metastatic breast cancer.In a Phase 1 study, data were reported from 53 patients (35 with TNBC) with LIV-1-expressing MBC who were treated with SGN-LIV1A monotherapy administered every three weeks. Patients had received a median of four prior systemic therapies for metastatic disease. Among evaluable TNBC patients, 37% achieved a partial response (PR). The disease control rate (DCR), defined as patients achieving a complete response (CR), PR or stable disease (SD), was 67% and the clinical benefit rate (CBR), defined as patients achieving CR or PR of any duration plus patients achieving SD lasting at least 24 weeks, was 47%.At the time of an interim data analysis, the estimated median progression-free survival for metastatic triple-negative breast cancer patients was 12 weeks, with seven patients remaining on treatment. (As of Dec. 2017, clinical trials for this drug are underway).From: https://adcreview.com/news/sgn-liv1a-monotherapy-data-show-37-orr-heavily-pretreated-triple-negative-metastatic-breast-cancer/

d. Clinical Trials for BRCA1/2 Positive MBC:

Talazoparib: The Phase 3 EMBRACA trial for patients with germline (inherited) BRCA1/2-positive locally advanced and/or metastatic breast cancer demonstrated superior progression-free survival (PFS) in people treated with Talazoparib, compared to patients who received physician's choice standard of care chemotherapy.The median PFS was 8.6 months for patients treated with Talazoparib vs. 5.6 months for those treated with chemotherapy.This represents a 46% reduction in the risk of disease progression.In addition, the proportion of patients achieving a complete or partial response (objective response rate) in the Talazoparib group was more than twice that of the control arm (62.6% for the Talazoparib group vs. 27.2% for the chemotherapy group). From:https://www.businesswire.com/news/home/20171208005117/en/Talazoparib-Significantly-Extends-Progression-Free-Survival-Phase-3