Expert Expands on Emerging Developments in Metastatic TNBC

Therapeutic approaches for patients with metastatic triple-negative breast cancer (TNBC) have historically been chemotherapy. However, over the past year, the pipeline has exploded to include more ways of treating patients with this highly aggressive disease, including checkpoint inhibitor combinations and antibody-drug conjugates (ADCs). 

“We now have new options for the treatment of metastatic triple-negative breast cancer that has been recently approved by the FDA,” says Hatem Soliman, MD.

Most recently, in April 2020, the FDA granted an accelerated approval to the ADC sacituzumab govitecan-hziy (Trodelvy) for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.

In an interview with OncLive, Soliman, a medical oncologist specializing in breast cancer in The Center for Women’s Oncology and a member of the Experimental Therapeutics Program at Moffitt Cancer Center, elaborated on a number of promising agents available and emerging in mTNBC.

OncLive: Could you expand on the rationale for the use of immunotherapy in TNBC?

Soliman: The rationale for using [immunotherapy in TNBC] stems from understanding the differences in biology between different subtypes of breast cancer. We realize that certain types of breast cancer are more prone to stimulating a reaction from the host immune system and, in some cases, it's due to how different the tumor is from normal breast tissue. Hormone receptor–positive breast cancers, particularly those that are well differentiated and low grade, tend to act more like normal breast tissue, unless they elicit a very strong host immune response. Tumors are aggressive in biology and are very abnormal due to the various mutations they've acquired. In the beginning, the high proliferation rates can trigger or elicit a fairly potent host immune response.

TNBC does seem to harbor more of those aggressive subtypes, which can elicit infiltration of tumor lymphocytes. It’s thought that those tumors that are somewhat inflamed, rather than those that are considered immunologic deserts, are prime targets for checkpoint therapy such as atezolizumab (Tecentriq) or pembrolizumab (Keytruda). In a nutshell, that is some of the rationale behind why TNBC in particular; it is biologically attractive. Most of the objective activity that was observed in the early stages occurred in TNBC, as opposed to HR-positive cases. This is why we may be seeing more emphasis placed on investigation when it comes to checkpoint therapy in patients with TNBC.

What are some other pivotal studies in this space, and why were the findings significant?

KEYNOTE-086 looked at the use of pembrolizumab in TNBC as monotherapy. The trial was subdivided into 2 cohorts: cohorts A and B. Cohort A had a lot more chemotherapy-pretreated patients. [In this cohort, pembrolizumab] did not appear to have very significant single-agent activity; the response rate was roughly around 4.7% so it didn't make the 5% cutoff. Whereas, [cohort B included patients who received] pembrolizumab in the first line-setting. The response rate climbed up to 23%. It appeared that patients whose immune systems were less battered from immunotherapy or prior treatments were more likely to respond to checkpoint therapy, which was interesting.

This leads into some of the other studies, including IMpassion130 and KEYNOTE-355. IMpassion130 covered [first-line atezolizumab in] metastatic TNBC. They enrolled a little over 900 patients and randomized them 1:1 between 2 arms. These 2 arms were either nab-paclitaxel (Abraxane), given 100 mg/m2, and atezolizumab, given every other week at 840 mg, versus placebo plus nab-paclitaxel at the same dose. In the intent-to-treat (ITT) population, there did appeared to be a statistically significant positive signal for an improvement in progression-free survival (PFS). There was a hazard ratio of .8 and the P value was .0025. Overall survival (OS) did not meet the threshold for statistical significance in the ITT population.

However, when looking at the PD-L1–positive group, we saw the same PFS with an improvement in hazard ratio down to 0.62. However, you also then saw an emerging OS improvement as well. Patients whose tumors were PD-L1 positive had a hazard ratio of about 0.45. The data that were published in the New England Journal of Medicine led to the approval of atezolizumab plus nab-paclitaxel for metastatic first-line TNBC. Some of the [updated data] confirmed that there wasn't a substantial benefit for median OS in the PD-L1–positive group and confirmed that there was no benefit in terms of OS in the PD-L1–negative group. PD-L1 positivity was defined as at least 1% or more immune-infiltrating cells staining positive for PD-L1 expression. This [approval] in the metastatic TNBC space for immunotherapy paved the way for additional investigations in the space.

KEYNOTE-355 also looked at first-line metastatic TNBC treatment. A slight difference in the IMpassion130 trial is that they permitted patients who were no more than 6 months out from their last prior therapy. In essence, if they had relatively refractory disease, they were allowed to enroll in KEYNOTE-355 as opposed to IMpassion130. About 847 patients were randomized 2:1 to pembrolizumab and their choice of chemotherapy. The [primary end point] was PFS. The results of the trial showed that in those patients with combined positive score (CPS) scores greater than 10, there did appear to be a significant PFS advantage.

Could you speak to the emergence of ADCs in TNBC?

ADCs have been around now for several years as a platform to help us deliver, with great precision and accuracy, toxic payloads to tumor cells that otherwise would be too toxic to give to our patients. It allows us to potentially salvage drugs that may have great antitumor activity but, unfortunately, it would have been too toxic to give through regular intravenous or oral administration. That's the key of ADCs; their therapeutic benefit is based on how well they deliver potent toxic waste drugs to cancer cells while sparing normal tissues from high concentrations of three drugs. They improve the therapeutic index and quality of life for these patients who are on therapy.

Now, resistance to some of these drugs could potentially develop because either the tumor cells become resistant to the payload that's attached to the antibodies, or they may downregulate the target that the antibodies attach to. Many researchers and companies have been finding a variety of different cell targets that could serve as important therapeutic targets to land these toxic payloads via an antibody bind to the tumor cells. These cell targets leave normal tissue alone. The key factor in selecting tumor proteins is that they're much more highly expressed in malignant tissue than in normal cells.

One example of an ADC that has been around for a while in the HER2 space is ado-trastuzumab emtansine (T-DM1; Kadcyla), which takes an anti-HER2 antibody conjugated to an MMAE payload, an anti-microbial agent that is very potent but too toxic to give without conjugating to the antibody, which has been used in the second-line setting for some time. Now, more recently, with the KATHERINE data, it's been moved up into the curative setting for women who did not achieve a pathologic complete response to neoadjuvant anti-HER2 therapy.

We now [another] option for TNBC treatment that has been recently approved by the FDA. This is an ADC called sacituzumab govitecan that targets a cell surface protein called Trop-2, which is highly expressed in a larger number of TNBC cells and other tumor types, but relatively less expressed in normal tissue. That makes Trop-2 an attractive target for the strategy. Instead of attaching MMAE to the antibody, they attached an agent known as SN-38, which is one of the metabolites of irinotecan that's been in use for quite some time for tumors, such as colorectal cancer. The recent approval for sacituzumab govitecan is for TNBC after progression on 2 prior lines of therapy in the metastatic setting.

The data that was used by the FDA to approve this drug was stemming from an early phase 1/2 trial published in 2019 in the New England Journal of Medicine, which showed a very encouraging response rate in patients heavily pretreated with TNBC. The median number of treatments for this population was 3. Anyone who treats patients with metastatic TNBC, especially in cases where they know they've been treated with a number of prior therapies, understands that it’s a very difficult disease to get a meaningful or durable response from.

Therefore, for the investigators to see the degree of response that was observed in the trial, with over one-third of the patients having some form of an objective response and about 50% of patients having either stable disease or minor shrinkage, this proved to be an exciting new agent for women with hard-to-treat metastatic TNBC.

Another advantage of the drug was that some of the responses were very durable. When you look at some of the swimmer plots, some of them were ongoing out to 36 months. This is an exciting option for women with TNBC. Recently, we heard news that the confirmatory phase 3 trial for this drug was halted by the Data and Safety Monitoring Board for positive results. It appears that the confirmatory study may back up this activity that we saw in the early phase 1/2 trial and hopefully will cement the role of sacituzumab govitecan in the treatment of patients with TNBC, both in the salvage setting but potentially maybe even earlier on as it's combined with other agents.