Vital developments have been made focusing on the as soon as “targetless” subtype of breast most cancers—triple-negative breast most cancers (TNBC)—as identifiable targets are being exploited to enhance affected person outcomes, in accordance with Sara M. Tolaney, MD, MPH.
Notably, combining checkpoint inhibitors with chemotherapy has proven promise, particularly in sufferers with PD-L1–constructive metastatic TNBC, as demonstrated by findings from the part 3 KEYNOTE-355 trial (NCT02819518), which revealed pembrolizumab (Keytruda) plus chemotherapy improved progression-free survival (PFS) and total survival (OS) vs placebo plus chemotherapy. Nevertheless, no profit was noticed in sufferers with PD-L1–detrimental tumors.1 Moreover, latest knowledge introduced on the 2024 American Society of Medical Oncology Annual Assembly confirmed that PARP inhibitors could also be a promising technique in TNBC. An growth cohort of the part 3 OlympiA trial (NCT0203282324) included 24 sufferers with breast most cancers and germline PALB2 mutations, and among the many 2 sufferers with TNBC, each skilled a response to therapy with olaparib (Lynparza) monotherapy.2
“We’ve outlined TNBC, sadly, by what it isn’t quite than what it’s. TNBC has been outlined as being detrimental for the estrogen receptor, progesterone receptor, and HER2, whereas there are targets which might be current [for] triple-negative illness,” Tolaney stated in an interview with OncLive® following an OncLive State of the Science Summit, which she chaired. “We’ve come a good distance from a subtype of breast most cancers that was as soon as considered targetless, to at least one that has a number of targets. We at the moment are profiting from that and utilizing that to enhance outcomes for our sufferers.”
Within the interview, Tolaney mentioned the transformation of therapies for TNBC and expanded on her interpretation of information from the KEYNOTE-355 trial. Tolaney is chief of the Division of Breast Oncology and affiliate director of the Susan F. Smith Middle for Ladies’s Cancers; she additionally serves as a senior doctor at Dana-Farber Most cancers Institute and an affiliate professor of drugs at Harvard Medical College, all in Boston, Massachusetts.
OncLive: What’s the rationale for combining checkpoint inhibitors with chemotherapy?
Tolaney: We have been initially upset by the efficacy of immunotherapy in triple-negative illness; we tried utilizing checkpoint inhibitors as monotherapy and noticed that solely a small subset of sufferers derived profit from a checkpoint inhibitor given alone. There was a variety of curiosity in seeing what we may do to make immunotherapy more practical, and one thought was that combining a checkpoint inhibitor with chemotherapy may make [treatment] more practical.
The rationale was that the chemotherapy goes to kill the most cancers cells, launch antigens, after which enable the immune system to acknowledge the most cancers and work synergistically with the chemotherapy. It seems that was true as a result of whenever you use chemotherapy with checkpoint inhibition, [the doublet] does significantly better than chemotherapy alone. Nevertheless, it solely does [better in terms of efficacy] in sufferers who’ve PD-L1–constructive metastatic triple-negative illness. If the tumor doesn’t specific PD-L1, then the checkpoint inhibitor is just not including further profit. In that sense, we’re slightly bit restricted [with options as] roughly 40% of sufferers who’ve metastatic TNBC can have tumors which might be PD-L1–constructive, so [the doublet] is just not benefiting all sufferers with triple-negative metastatic illness.
What key knowledge must be famous on checkpoint inhibitor mixtures in TNBC?
The KEYNOTE-355 trial randomly assigned sufferers with metastatic TNBC who had not acquired any remedy within the metastatic setting for triple-negative illness to chemotherapy of doctor’s selection which may very well be a taxane or carboplatin and gemcitabine vs chemotherapy of doctor’s selection with pembrolizumab.
On the time the trial was carried out, we didn’t know that checkpoint inhibitors have been solely going so as to add profit within the metastatic setting for sufferers who had PD-L1–constructive tumors. Due to this fact, the trial was designed to look not simply at sufferers who had tumors that have been PD-L1–constructive, but additionally to have a look at the general affected person inhabitants. Knowledge confirmed that there was an enchancment in each PFS in addition to OS in sufferers with PD-L1–constructive tumors, however no profit in these with PD-L1–detrimental tumors.
The cut-off that was used to outline positivity for PD-L1 was utilizing a [PD-L1 IHC] 22C3 assay and a mixed constructive rating [CPS] that was better than or equal to 10. We’re all the time trying to see if the CPS rating is 10 or larger to know if a affected person is a candidate for pembrolizumab with chemotherapy.
What’s essential to find out about focusing on DNA restore?
In breast most cancers, the medicine which have been accredited for focusing on DNA restore are PARP inhibitors and they’re solely at the moment accredited within the metastatic setting for sufferers who’ve a germline BRCA mutation. If sufferers have a germline BRCA mutation both talazoparib [Talzenna] or olaparib are very efficient on this setting. When these brokers have been in contrast head-to-head with chemotherapy, [they] win when it comes to enhancing PFS. Nevertheless, I used to be slightly upset as a result of when PARP [inhibitors are] in contrast with chemotherapy, they don’t seem to be superior when it comes to OS. There may be nonetheless room for enchancment.
We do know, nonetheless, that it’s not simply sufferers with germline BRCA mutations who profit [from these agents]. Rising knowledge that got here out from the olaparib expanded trial confirmed that sufferers who’ve germline PALB2 mutations in addition to sufferers who’ve somatic BRCA alterations additionally derive profit from PARP inhibition. In my apply, I’ll use a PARP inhibitor in a affected person who has germline PALB2, somatic BRCA, or germline BRCA [mutations]. There are different brokers in growth, equivalent to PARP1 selective inhibitors, so we’ll see extra about the place these brokers transfer [in the treatment landscape].
References
- Cortes J, Rugo HS, Cescon DW, et al; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in superior triple-negative breast most cancers. N Engl J Med. 2022;387(3):217-226. doi:10.1056/NEJMoa2202809
- Tung NM, Robson ME, Nanda R, et al. TBCRC 048 (olaparib expanded) growth cohorts: Section 2 research of olaparib monotherapy in sufferers (pts) with metastatic breast most cancers (MBC) with germline (g) mutations in PALB2 or somatic (s) mutations in BRCA1 or BRCA2. J Clin Oncol. 2024;42(suppl 16):1021. doi:10.1200/JCO.2024.42.16_suppl.1021
