TNBC Treatment Paradigm Advances With the Rise of Chemoimmunotherapy Combos

Several novel chemoimmunotherapy combinations have risen to the forefront of treatment in triple-negative breast cancer (TNBC), according to Neelima Vidula, MD. However, what the optimal chemotherapy backbone is, which PD-L1 assay should be utilized, and whether this approach will play a role in the neoadjuvant setting are all questions that remain unanswered.

“Some of the initial studies that were done in advanced TNBC evaluated immunotherapy as a monotherapy; however, these studies only showed a modest benefit,” said Vidula. “As a result, in recent years, several studies have looked at combination therapy, mainly combining chemotherapy with immunotherapy, [to some success].”

The addition of the PD-L1 inhibitor atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane), which reduced the risk of progression or death by 40% versus nab-paclitaxel alone in patients with unresectable locally advanced or metastatic PD-L1–positive TNBC.¹ These data from the pivotal phase 3 IMpassion130 trial supported the FDA’s decision in March 2019 to approve the combination for use in this patient population.

More recently, in November 2020, the FDA granted accelerated approval to pembrolizumab (Keytruda) in combination with chemotherapy in patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 with a combined positive score (CPS) of 10 or greater after the regimen resulted in a median progression-free survival (PFS) of 9.7 months versus 5.6 months with chemotherapy alone in the phase 3 KEYNOTE-355 trial.²

In an interview with OncLive^® during the 2020 OncLive Institutional Perspectives in Cancer webinar on Breast Cancer, Vidula, a breast medical oncologist at Massachusetts General Hospital, highlighted some of the pivotal trials evaluating immunotherapy combination regimens, some of the challenges faced in practice, and areas for further exploration.

OncLive^®: With regard to immunotherapy, could you speak to some of the data from the pivotal IMpassion130 and KEYNOTE-355 trials? How you are applying this knowledge to practice?

Vidula: The IMpassion130 study is quite notable. This study took patients with advanced TNBC who did not receive any previous therapy for advanced disease and randomized them in a 1:1 fashion to atezolizumab, an anti–PD-L1 antibody, and nab-paclitaxel or nab-paclitaxel alone. As a part of this study, a stratification analysis by tumor PD-L1 immune cell status was also done.

The take-home message from this study was that there was an improvement in overall survival [OS] in the population of patients whose tumors were PD-L1 positive with the addition of atezolizumab to nab-paclitaxel versus nab-paclitaxel alone. The median OS improved to 25 months versus 17.9 months in the control group. As a result of these pivotal findings, the combination has been FDA approved for patients with metastatic TNBC whose tumors are PD-L1 immune cell positive, so this was a very exciting advancement. It’s important for patients who have advanced TNBC to undergo PD-L1 testing on their tumor at the time of metastatic diagnosis, since this creates a treatment option for them. 

During the 2020 ASCO Virtual Scientific Program, results from another phase 3 trial, KEYNOTE-355, were presented. Similarly, in this trial, patients with advanced TNBC were randomized to pembrolizumab, an anti–PD-1 antibody, and chemotherapy, which could include a taxane or gemcitabine and carboplatin versus chemotherapy alone. We saw that, in tumors that were PD-L1 positive, defined by a CPS of above 10, there was a PFS improvement with the addition of pembrolizumab to standard chemotherapy.

These data are very interesting, and [as] expected, pembrolizumab [recently received] FDA approval for use in this setting; this [provides an] additional treatment option for patients with metastatic TNBC whose tumors are PD-L1 positive. 

Based on data that are currently available from these different trials, is there an optimal chemotherapy backbone that should be used?

The IMpassion130 study showed a very promising improvement in survival with the combination of atezolizumab and nab-paclitaxel. However, more recently, there was also the IMpassion131 study, which combined paclitaxel with atezolizumab, compared with paclitaxel alone. These data were also presented during the 2020 ESMO Virtual Congress.

Unfortunately, this study did not show an improvement in OS in patients who had PD-L1–positive tumors. We're still trying to understand the data from this study, although, one potential explanation for this discrepancy is that the patients in the IMpassion131 study received steroids with paclitaxel, which may have dampened their immune response.

With that said, in the KEYNOTE-355 study, investigators did look at a variety of chemotherapy partners in combination with pembrolizumab; this could include a taxane or gemcitabine and carboplatin. The taxane could include agents such as abraxane or paclitaxel. As previously mentioned, there was an improvement in PFS with the addition of pembrolizumab to chemotherapy in tumors that had a CPS score >/=10. Based on the data that are currently available, atezolizumab and nab-paclitaxel is approved for patients with TNBC who have PD-L1–positive tumors. As such, I would strongly consider using that combination when treating patients in this setting.

The KEYNOTE-355 data suggest that pembrolizumab in combination with a different chemotherapy partner could potentially be beneficial…If there is a patient who recently received a taxane in the adjuvant setting and had an early recurrence, I may consider administering immunotherapy in combination with a different chemotherapy partner. Based on the data from IMpassion131, I would stay away from using paclitaxel as the chemotherapy partner; instead, I would try other agents like gemcitabine or carboplatin. 

Now that pembrolizumab is approved in the advanced setting, are you anticipating any challenges evaluating PD-L1 expression, considering it will have a different assay?

One major challenge is that almost every study that has been conducted has used a different PD-L1 assay. For example, the IMpassion130 study defined PD-L1 positivity on the immune cells as greater than 1%, while other studies used various other assays. The KEYNOTE-355 study defined PD-L1 positivity by CPS score. So, this is a challenge because it’s not clear which assay we should be using. Every institution also has their own in-house assays, so that makes it tricky.

Currently, I believe that any assay that you are able to access should be used. Since IMpassion130 is the study that led to the FDA approval, I would try to use the VENTANA PD-L1 (SP142) assay if you’re able to, since there is an approval in that setting. However, there's no clear data on how these assays all line up against each other and whether findings with 1 assay will translate into a benefit [over] another assay.

Immunotherapy is also being evaluated in the neoadjuvant setting, although data have been mixed. How are you reconciling these results?

I believe there is a similar degree of confusion here. Right now, I would probably not use immunotherapy in the neoadjuvant or adjuvant setting outside of a clinical trial. Certainly, the KEYNOTE-522 data are quite compelling and, if there is an FDA approval, it may become an option for patients.

In the adjuvant and neoadjuvant settings, we need to balance toxicity with benefit because if patients are anticipated to have a good outcome, we don't want to have them incur long-term toxicity from immunotherapy. I would be very careful when selecting patients. For example, I would most likely choose patients who are at higher risk, have a larger tumor, are of a younger age, or have a lot of nodal involvement. 

References

1. Schmid P. IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2018;29(suppl 8):707-708. doi:10.1093/annonc/mdy424.008
2. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. News release. FDA. November 13, 2020. Accessed November 13, 2020. https://bit.ly/3nqbQ5s. 

Editor’s Note: This interview was conducted prior to the November 13, 2020 FDA approval of pembrolizumab in combination with chemotherapy in patients with locally recurrent unresectable or metastatic TNBC.