Putting Immune Checkpoint Blockade to the Test in Breast Cancer

About 10 months ago, we asked: Is There a Future for Immunotherapy in Breast Cancer? Now, we can answer this question with a qualified “yes.” The data show why:

Triple-negative breast cancer (TNBC)

TNBC has long been considered to be more amenable to immune system-based treatments than other types of breast cancer because it is more immunogenic; that is, relatively high levels of immune cells accumulate within or adjacent to TNBC tumors. These immune cells could be triggered to attack tumors if properly activated. TNBC tumors are also likely to have a higher mutational burden (number of genetic mutations). This is one of the predictors of sensitivity to a type of treatment called immune checkpoint blockade.  Drugs known as checkpoint inhibitors block the proteins PD-1 or PD-L1. In cancer, PD-L1 proteins on tumor cells bind to PD-1 proteins on immune T cells and inhibit their tumor-killing activity. Immune checkpoint drugs disable this interaction and enable activation of T cells. These drugs are actively being explored in TNBC in clinical trials.

In the KEYNOTE-012 trial, the anti-PD-1 drug Keytruda showed an overall response rate (ORR) of 18.5% in patients who were selected based on the presence of PD-L1 in their tumors. (ORR is the percentage of patients who experienced some reduction in tumor burden within the trial timeframe.) Atezolizumab, an anti-PD-L1 drug, produced a similar ORR (19%) in a group of TNBC patients; half of the responses in this trial were complete.

While very promising, these numbers fall short of a really high rate. However, preliminary results were reported in December from a trial that combined atezolizumab with nab-paclitaxel, a chemotherapy drug often used to treat TNBC. The ORR in this trial was 42%, which is great rate for metastatic TNBC. It is also worth noting that in nine patients who had not received previous treatments, the ORR was even higher; at 67%, it is higher than any other ORR seen previously in TNBC. Based on this result, a new study called Impassion 130 (NCT02425891) is now enrolling TNBC patients who have not received prior treatments.

Avelumab, another drug that targets PD-L1, induced responses in about 17% of TNBC patients in the JAVELIN trial. Patients whose tumors expressed PD-L1 had a significantly higher response rate (44%). Yet another anti-PD-L1 drug, durvalumab, is in trials for breast cancer, as is the anti-PD-1 drug nivolumab (Opdivo).

Hormone receptor-positive/HER2-negative (ER+/HER2-) cancers

In the KEYNOTE-028 trial, Keytruda elicited partial or complete responses in about 12% of patients with ER+ cancers expressing PD-L1. This is lower than in TNBC, but apparently, responses were just as durable as those seen in TNBC. A low ORR (2.8%) for ER+ cancers was documented in the JAVELIN trial, which explored avelumab in breast cancer regardless of PD-L1 expression. The underlying reason for the low ORR could be that tumor PD-L1 expression is found in only 19% of patients with ER+ cancers.

HER2-positive (HER2+) cancers

These cancers are routinely treated with HER2-targeted drugs—such as trastuzumab (Herceptin) or T-DM1 (Kadcyla)—and chemotherapy. The limited results of trials testing avelumab in HER2+ cancers are not very promising so far, but a recent preclinical study provides a glimmer of hope. It showed that in a mouse model, treatment with T-DM1 in early-stage HER2+ cancers induces a massive influx of immune T cells into the tumors. Moreover, adding the older immune checkpoint drug ipilimumab (Yervoy) to T-DM1 in this mouse model eliminated tumors completely. These findings open the possibility that combining HER2-targeted drugs with checkpoint drugs may have activity against HER2+ cancers.

Clinical trials

It is clear that, among breast cancer subtypes, TNBC shows the most promise as a target for immune checkpoint drugs. It is also evident that the main thrust in further exploring this strategy is to find the best drugs to administer along with checkpoint drugs in the hope of nudging the rate of response higher. This approach is being explored in clinical trials for HER+ and ER+ breast cancers, albeit with lower intensity than in TNBC.

The table below lists clinical trials that are testing checkpoint drugs, often in combination with chemotherapy, targeted therapy, or additional immunotherapy drugs. There is hope that some of these will report encouraging results:

Trial number Drug I (anti-PD-1 or PD-L1) Drug II Type of cancer Notes
NCT02447003 Keytruda TNBC
NCT02513472 Keytruda Eribulin (chemo) TNBC
NCT02555657 Keytruda or chemotherapy Randomized
NCT02657889 Keytruda Niraparib (targeted) TNBC Not open yet
NCT02499367 Opdivo Radiation, chemotherapy TNBC Only in The Netherlands
NCT01928394 Opdivo Ipilimumab (immune) or placebo TNBC
NCT02425891 Atezolizumab or placebo Nab-paclitaxel (chemo) TNBC, no previous treatments Randomized
NCT02543645 Atezolizumab Varlilumab (immune) TNBC
NCT02655822 Atezolizumab or placebo CPI-444 (targeted) TNBC Randomized
NCT02628132 Durvalumab Paclitaxel (chemo) TNBC Not open yet
NCT02453620 Opdivo Ipilimumab (immune), entinostat (targeted) ER+/HER2- Accepts stage III and IV
NCT02309177 Opdivo Nab-paclitaxel (chemo) ER+/HER2- Not open yet
NCT02648477 Keytruda Endocrine therapy ER+/HER2- Not open yet
NCT02129556 Keytruda HER2+, resistant to Trastuzumab
NCT02649686 Durvalumab Trastuzumab (targeted, HER2) HER2+ Not open yet
NCT02411656 Keytruda Inflammatory
NCT02643303 Durvalumab Tremelimumab (immune), vaccine Any, locally recurrent Not open yet
NCT01772004 Avelumab All