Changes Bring Immunotherapy to the Forefront of the Breast Cancer Treatment

Rita Nanda, MD

Immunotherapy may become one of the most prevalent forms of therapy for breast cancer, explained Rita Nanda, MD, during a presentation at the 2019 Lynn Sage Breast Cancer Symposium.¹

Nanda, director of the Breast Oncology Program at the University of Chicago in Illinois, began by reviewing the modest response rates checkpoint inhibitors have achieved as monotherapy in breast cancer. The objective response rate (ORR) ranged from a high of 23% in patients with triple-negative breast cancer (TNBC) with pembrolizumab (Keytruda) to 10% in the same population with atezolizumab (Tecentriq) and about 5% in all subtypes with avelumab (Bavencio), she said.

“In terms of monotherapy, ORR for metastatic TNBC, for patients who get a frontline checkpoint inhibitor, the response rates are around 25%, but ORR drops to around 5% in the second-line-plus setting,” Nanda said. “What we’ve learned from some of the initial studies is that line of therapy matters.”

Noting that the frontline ORR is comparable to that obtained via chemotherapy, Nanda added that responses are more durable with atezolizumab or pembrolizumab when stratified by PD-L1 status. Additionally, higher ORR and overall survival (OS) are seen in patients with higher tumor-infiltrating lymphocytes who receive atezolizumab monotherapy, she said.

Combination Regimens Show Promise

In addressing combined regimens, Nanda offered a rationale for combining checkpoint inhibitors with chemotherapy.

“Priming of T cells requires antigen presentation by dendritic cells, and not all mechanisms of cell death are the same,” Nanda said. “Apoptosis is immunologically silent, and immunogenic cell death facilitates antigen uptake by dendritic cells, and chemo induces lymphodepletion.”

That led to Nanda&rsquo;s discussion of IMpassion130, which compared nab-paclitaxel (Abraxane) with and without atezolizumab in a randomized double-blind trial of patients with TNBC who have metastatic or locally advanced inoperable disease. Patients were stratified by prior taxane use, the presence or absence of liver metastases, and PD-L1 status (positive [&ge;1%] vs negative [<1%]). The co-primary endpoints were progression-free survival (PFS) and OS in the intention-to-treat and PD-L1—positive populations. The investigators also evaluated ORR and duration of response as secondary efficacy endpoints.²

In the trial population as a whole, the median PFS was 7.2 months in the atezolizumab group compared with 5.5 months in the placebo group (stratified HR, 0.80; 95% CI, 0.69-0.92;P= .0025). In the general trial population, the median OS was 21.3 months compared with 17.6 months, respectively (stratified HR, 0.84; 95% CI, 0.69-1.02;&nbsp;P= .0840).

The results were comparable in the PD-L1—positive group. The median PFS was 7.5 months in the experimental group versus 5.0 months in the control group (stratified HR, 0.62; 95% CI, 0.49-0.78;P<.0001). The median OS was 25.0 months for the atezolizumab group versus 15.5 months in the placebo group (stratified HR, 0.62; 95% CI, 0.45-0.86).

The atezolizumab/nab-paclitaxel combination is FDA approved for the frontline treatment of patients with PD-L1—positive metastatic TNBC. &ldquo;PD-L1 is not a perfect biomarker, and the current testing has challenges, which is why clinicians should only use the Ventana SP142 assay,&rdquo; Nanda said.

Trials with nontaxane chemotherapy backbones also appear promising, Nanda added, especially those that use antibody—drug conjugates.

Nanda also noted that PARP inhibition may enhance immune surveillance through multiple mechanisms, stimulating immunologically &ldquo;cold&rdquo; tumors to become immunologically &ldquo;hot&rdquo; tumors via cell death—mediated inflammation and increased neoantigen load.

In particular, Nanda focused on the TOPACIO phase II trial, which combined the PARP inhibitor niraparib (Zejula) with the checkpoint inhibitor pembrolizumab.³In this trial, which included 47 evaluable patients with a variety of homologous recombination repair/DNA damage repair (HRR/DDR) mutations, nearly half of patients derived clinical benefit from the regimen. This included 10 patients with a&nbsp;BRCA1/2mutation, 8 with no&nbsp;BRCA1/2mutation, and 4 with other mutations in HRR/DDR.

NanoString profiling by TOPACIO investigators revealed 36 genes that were differentially expressed in patients with clinical benefit (P<.05), said Nanda. &ldquo;It was also noteworthy that PD-1 expression, but not PD-L1 expression, was associated with clinical benefit,&rdquo; she said.

Other notable findings from TOPACIO were that &ldquo;those with clinical benefit had higher T-cell—inflamed gene expression profile [GEP], and those with benefit had higher T-cell&ndash;inflamed GEP regardless of mutation status,&rdquo; Nanda added.

Nanda also discussed the potential of MEK inhibitors in patients with TNBC. Because the MEK pathway is active in TNBC, activation suppresses inflammatory responses to T cells, including reduced antigen presentation and decreased PD-L1 expression. &ldquo;Combining a MEK inhibitor with anti—PD-1/PD-L1 agents may improve antigen presentation and blocking PD-L1&ndash;mediated suppression,&rdquo; she said.

One trial exploring this strategy was the phase II COLET study, which explored the combination of atezolizumab and the MEK inhibitor cobimetinib (Cotellic) plus either paclitaxel or nab-paclitaxel as first-line treatment in advanced TNBC. COLET&rsquo;s primary endpoint was ORR.⁴

Among all patients, the response rate was 39% (12 of 31) for PD-L1—positive patients and 20% (4 of 20) for the PD-L1&ndash;negative group. In the paclitaxel group, 44% (7 of 16) of patients with PD-L1&ndash;positive disease responded, whereas only 11% (1 of 9) of PD-L1&ndash;negative patients responded. In the nab-paclitaxel group, 33% (5 of 15) of PD-L1&ndash;positive patients responded, whereas 27% (3 of 11) of PD-L1&ndash;negative patients responded.

Nanda summed up her wide-ranging presentation by noting that exciting new treatment approaches for TNBC abound. &ldquo;We&rsquo;re seeing that everything can be combined with immunotherapy,&rdquo; she said. &ldquo;We&rsquo;re also learning that moving treatment to the early-stage setting is critical.&rdquo;

References:

1. Nanda R. Immunotherapy for breast cancer: the future is now. Presented at: Lynn Sage Breast Cancer Symposium; October 3-6, 2019; Chicago, IL.
2. Schmid P, Adams S, Rugo HS, et al; Impassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.
3. Vinayak S, Tolaney SM, Schwartzberg L, et al. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162). Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018. San Antonio, TX. Abstract PD5-02.
4. Brufsky A, Kim S-B, Zvirbule Z, et al. Phase II COLET study: atezolizumab (A) + cobimetinib (C) + paclitaxel (P)/nab-paclitaxel (nP) as first-line (1L) treatment (tx) for patients (pts) with locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2019;37(suppl 15):1013. doi: 10.1200/JCO.2019.37.15_suppl.1013.