Bhave Spotlights Breakthroughs Made With Immunotherapy Combinations in TNBC

Manali Bhave, MD

Chemoimmunotherapy has become the standard of care for the frontline treatment of patients with PD-L1–positive, locally advanced or metastatic triple-negative breast cancer (TNBC). However, understanding which patients will derive the most benefit from the approach, whether there is an optimal immunotherapy agent that should be paired with the chemotherapy, and whether the chemotherapy backbone can be de-escalated are all areas in need of further exploration, according to Manali Bhave, MD.

“We have seen many exciting developments in the treatment of [patients with] TNBC, both in the early-stage and metastatic settings, particularly with regard to the use of immunotherapy in combination with chemotherapy,” Bhave said.

Among the most notable updates were the data that read out from the phase 3 KEYNOTE-522 (NCT03036488) and Impassion031 (NCT03197935) trials, according to Bhave.

Data from KEYNOTE-522 showed that pembrolizumab (Keytruda) plus chemotherapy resulted in a pathologic complete response (pCR) rate of 64.8% (95% CI, 59.9%-69.5%) in patients with previously untreated stage II or III disease vs 51.2% (95% CI, 44.1%-58.3%) with placebo/chemotherapy, translating to a difference of 13.6 percentage points (P <.001).1 In those with PD-L1 positivity, the pCRs were even higher, at 68.9% and 54.9%, respectively.

The combination of atezolizumab (Tecentriq) plus chemotherapy elicited a pCR rate of 58% (95% CI, 50%-65%) vs 41% (95% CI, 34%-49%) with placebo/chemotherapy in patients with early-stage TNBC enrolled to the IMpassion031 trial; this translated to a rate difference of 17% (P = .0044).2 In those with PD-L1 positivity, the pCR rates in the investigative and control arms were 69% and 49%, respectively.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Breast Cancer, Bhave, an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, discussed the role of immunotherapy in early- and advanced-stage TNBC, combinations under investigation, and important areas of ongoing research.

OncLive®: What is the state of immunotherapy in the early-stage and metastatic breast cancer settings?

Bhave: For the treatment of [patients with] early-stage TNBC, [we have seen] updates from 2 trials. The phase 3 KEYNOTE-522 trial looked at the combination of pembrolizumab plus paclitaxel and carboplatin or placebo plus paclitaxel and carboplatin. The 2 arms received additional cycles of pembrolizumab or placebo and both were given doxorubicin and cyclophosphamide or epirubicin and cyclophosphamide.

[The trial] randomized women who had higher-risk TNBC, so those with T1c, N1 or N2, or with more advanced disease, larger tumors and more nodes involved. [Results] showed a statistically significant improvement in pathological complete response [pCR] rates and that improvement was about 14% to 15%. Also, a subset analysis examined the PD-L1 population and found a statistically significant improvement in pCR rates [with pembrolizumab] that were higher in the PD-L1 group. That pCR rate went from about 55% to close to 70% in women with PD-L1 positivity, and from 30% to 45% in women who were PD-L1 negative.

The trial also looked at event-free survival and noted a trend toward improvement [with pembrolizumab]. Some of that survival data are still immature and pending, but again, [we saw] a very favorable trend. At the 18-month mark, 91% of women who had received immunotherapy had no breast cancer recurrence vs about 85% of those who did not receive immunotherapy.

[Additionally], in the phase 3 IMpassion031 trial, which looked at the addition of atezolizumab to nab-paclitaxel [Abraxane], doxorubicin, and cyclophosphamide for the treatment of [patients with] TNBC, we saw significant improvements in pCR rates, and those rates were actually improved by about 16.5% in all patients.

If these regimens are approved, do you imagine they would be indicated for that PD-L1 subset or for all comers?

Because we have seen improvements in pCR for all comers, I do believe that we will see an approval for all patients. The benefit [with this approach] is slightly higher in the PD-L1 population, but [we] still [see] an advantage of about 15% or so regardless of PD-L1 status. One of the interesting findings from KEYNOTE-522 is that [investigators] also looked at women who had node-positive disease and noted an absolute benefit of about 20%. Certainly, a higher rate of toxicity and of discontinuation [was observed] in the patients who had received the combination treatment.

We still have several questions that we need to answer. For example, we need to know which women would be most likely to tolerate and benefit from the combination of immunotherapy with chemotherapy. Also, is there a difference in terms of which immunotherapy we should be using between pembrolizumab and atezolizumab? No head-to-head comparison [has been done]. Finally, can we de-escalate the chemotherapy backbone? We know from prior trials that the anthracycline is an important part of potentially synergistically working with immunotherapy to enhance the pCR rates, but is the platinum really necessary? Without it, can we limit the toxicity but still see similar pCR rates?

How have the different methods for measuring PD-L1 positivity introduced challenges, and what do they suggest about what we know about PD-L1?

It is important to note that the use of immunotherapy is dependent on eligibility for the immunotherapy of choice, and also the assay that that assesses PD-L1 expression. With pembrolizumab, it is approved with an assay in the metastatic setting using a combined positive score. That differs from atezolizumab, which is approved with the Ventana [PD-L1 (SP142)] assay, which looks at PD-L1 status, particularly the immune cells.

From a logistic standpoint, it is very important to [know] that we can't use 1 assay with the incorrect immunotherapy; it has to be paired with the approved assay. It is also really important that academic institutions as well as local and community oncologists to understand [this], as well. There's no comparison in terms of whether 1 assay is more predictive of response to immunotherapy versus the other. It just happened to be what was paired with which immunotherapy. One thing we do know about TNBC is that there is a higher rate of PD-L1 expression, and that is one of the reasons why immunotherapy was such an exciting advancement for this group of patients.

What could ongoing trials, such as the phase 2 I-SPY-2 (NCT01042379), the phase 3 IMpassion031 (NCT03197935), and the phase 3 SWOG 1418 (NCT02954874), potentially offer to the early-stage setting?

From a preoperative standpoint, I-SPY-2 provides more of a precision medicine approach for the treatment of [patients with] early-stage TNBC. [The trial] utilizes molecular and imaging approaches to guide treatment, which is an exciting area to investigate. Patients will be sequenced prior to the initiation of their preoperative therapy, and then use potential mutational analysis to identify targets, which may provide higher rates of pCR. If we don't see that, then they are eligible for standard-of-care therapies, as well. [The trial] offers patients in the preoperative setting an exciting opportunity to get more of an adaptive precision approach to their treatment.

In terms of the adjuvant use of immunotherapy, these trials are also important because we don't necessarily know whether preoperative immunotherapy is better. In those women who did not receive preoperative immunotherapy, is it possible that we can still achieve durable, long-term responses if we give them adjuvant immunotherapy with either pembrolizumab through SWOG 1418, or atezolizumab through IMpassion031? It will also be interesting to get long-term data on these patients, because TNBC tends to occur in a younger population. We have to be mindful of potentially long-term immune-related toxicities and ensure that the benefits outweigh the risks associated with immunotherapy screening.

In the advanced setting, trials like the phase 3 KEYNOTE-355 (NCT02819518) and the phase 3 IMpassion130 (NCT02425891) have garnered interest. What is known about the longer-term follow-up from these efforts?

In KEYNOTE-355, [investigators] randomized patients with locally advanced unresectable or metastatic TNBC to either pembrolizumab plus 3 chemotherapy backbone options vs placebo and chemotherapy. The interesting part about this trial is that 3 different options for chemotherapy were allowed: nab-paclitaxel, paclitaxel, or carboplatin/gemcitabine. Over time, we've actually seen an advantage in progression-free survival [PFS] in all subgroups, including those who had lower levels of PD-L1; however, it was only statistically significant in women who had a combined positive score that was greater than, or equal to, 10. That PFS advantage was close to 4 months, so it went to about 9.7 months from 5.6 months, without immunotherapy. In these women who tend to have a median survival of about 12 months to 18 months, having that additional advantage is statistically and clinically very meaningful.

Also, a higher objective response rate [was observed] with the addition of immunotherapy in women who had a CPS score that was greater than or equal to 10, and durability of response [DOR] was also still significantly extended. The DOR, particularly, went to about approximately 19.3 months vs 7.5 months without immunotherapy. Again, this [approach] provides long periods of response that we do not see with just chemotherapy alone.

The update from IMpassion130, which was our first approval for immunotherapy in breast cancer, looked at atezolizumab and nab-paclitaxel in women with metastatic TNBC. We already knew that there was a PFS advantage for women who were PD-L1 positive, and that advantage was close 2.5 months, so this extended their PFS to 7.5 months. Also, a very clinically meaningful overall survival advantage [was observed with the investigative approach], at about 25 months vs 18 months without the use of immunotherapy.

Will immunotherapy be combined with PARP inhibitors or AKG inhibitors in this space? Could those approaches show comparable, if not superior, efficacy?

Hypothetically, it makes sense, scientifically, that the addition of some of these targeted agents will enhance the neoantigens in the body, and therefore, enhance the efficacy of immunotherapy in those patients. I'm very hopeful that we'll see long-term and durable responses with these combinations compared with any of these agents by themselves. The benefit of using a targeted therapy plus immunotherapy, versus chemotherapy is, hopefully, fewer toxicities. If we do see that, from a quality-of-life standpoint, that is going to make a big difference for our patients.

References

1. Schmid P, Cortes J, Puztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
2. Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind phase 3 trial. Lancet. 2020;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X