Investigators Tailor TNBC Therapy Using Genomic Alterations

Virginia G. Kaklamani, MD, DSc

Over the past few years, investigators in the breast cancer field have tried to find new ways to treat triple-negative breast cancer (TNBC) to produce longer survival durations and higher response rates. To do so, they have performed investigations into genomic pathways to target specific characteristics of a patient’s tumor for better results with treatments, such as PARP inhibitors and chemotherapies used in different sequences.

In a presentation at the 2020 Lynn Sage Breast Cancer Symposium, Virginia G. Kaklamani, MD, DSc, reviewed the current genomic tools in the TNBC landscape that predict response to targeted treatments, including AKT mutations, BRCA mutations, and homologous recombination deficiency (HRD).¹

“AKT can be activated by loss-offunction mutations, gain-of-function mutations, and so forth,” Kaklamani, the leader of the Breast Cancer Program at the University of Texas Health San Antonio MD Anderson Cancer Center, said. “AKT is an extremely important molecule in this PI3k pathway…the mTOR/PI3K/AKT pathway is being used [for] drugs such as AKT inhibitors to treat even TNBC.”

The PI3K/AKT pathway is one of the most frequently altered pathways in breast cancer and is key for the survival and growth of tumors. The agent ipatasertib selectively targets AKT mutations and was used in the phase 2 LOTUS trial (NCT02162719) for 124 patients with measurable locally advanced or metastatic TNBC. These patients had no prior systemic therapy for advanced and/or metastatic disease and had received no chemotherapy for at least 6 months.²

Patients were randomized to ipatasertib at 400 mg a day on days 1 to 21 in combination with paclitaxel at 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle versus paclitaxel and placebo dosed in a similar manner. The coprimary end points were progression-free survival (PFS) in the intention-to-treat (ITT) population and PIK3CA/AKT1/PTEN-altered population.

In the ITT group, the median PFS was 6.2 months with ipatasertib and 4.9 months with placebo (stratified HR, 0.60; 95% CI, 0.37-0.98). The 42 patients with PIK3CA/AKT1/PTEN-altered tumors by FoundationOne next-generation sequence testing had a median PFS of 9.0 months and 4.9 months with ipatasertib plus placebo, respectively (unstratified HR, 0.44; 95% CI, 0.20-0.99).

In the ITT group, the median PFS was 6.2 months with ipatasertib and 4.9 months with placebo (stratif ied HR, 0.60; 95% CI, 0.37-0.98). The 42 patients with PIK3CA/AKT1/PTEN-altered tumors by FoundationOne next-generation sequence testing had a median PFS of 9.0 months and 4.9 months with ipatasertib plus placebo, respectively (unstratified HR, 0.44; 95% CI, 0.20-0.99).

“Based on that trial, ipatasertib is now being looked at in phase 3 trials in TNBC,” Kaklamani said. This includes an ongoing phase 3 clinical trial (NCT04177108) of the drug in combination with atezolizumab (Tecentriq) for locally advanced or metastatic triple-negative disease.

In a similar design, the phase 2 PAKT study (NCT02423603) also looked at the PIK3CA/AKT1/ PTEN-altered population as a secondary end point of their trial. This trial investigated oral capivasertib at 400 mg twice daily on days 2 through 5, 9 through 12, and 16 through 19, plus paclitaxel at 90 mg/m² intravenously on days 1, 8, and 15; each cycle lasted 4 weeks. This was compared with paclitaxel and placebo. There were 140 patients with TNBC randomized 1:1 for the primary end point of investigator-assessed PFS in the ITT population.³

The PIK3CA/AKT1/PTEN-altered group (n = 28) showed significant improvement in PFS with a median of 9.3 months for those receiving capivasertib versus 3.7 months for those receiving placebo (HR, 0.30; 95% CI, 0.11-0.79; 2-sided P = .01). However, in patients who did not have altered tumors, the median PFS was 5.9 and 4.2 months, respectively, according to results published in 2020 (HR, 0.74; 95% CI, 0.50-1.08; 1-sided P = .06).

“This drug as well is being looked at in phase 3 trials as we speak,” Kaklamani added. “…PIK3CA mutations are being used now to predict response to a PI3K inhibitor and this is standard of care now for our clinic.”

Another way to look at the TNBC setting is through the predictive biomarker of HRD. “HRD assays can predict not only sensitivity to platinum [chemotherapy], but potentially sensitivity to PARP inhibitors,” Kaklamani said.

A pooled analysis of 5 phase 2 trials looking at patients with TNBC treated with neoadjuvant platinum-based chemotherapy showed that HRD can predict pathologic complete response (pCR) in these patients. In the analysis, patients with HRD tumors were more likely to achieve a pCR than those with nondeficient tumors at 44% versus 8%, respectively (P < .01).⁴

“HRD is predictive of chemotherapy benefit. All of these trials included a platinum [therapy]…. I think the bottom line from this is that when we use the HRD score, we can help predict chemotherapy benefit in the neoadjuvant setting,” Kaklamani said.

Kaklamani examined one of the trials (NCT01372579) to see if carboplatin and eribulin was efficacious in these patients. The investigators were “able to show this treatment had a 43.3% rate of residual cancer burden, which is relatively impressive for 4 cycles of chemotherapy that are also not anthracycline based,” she said. They were also looking at the residual cancer burden in patients with HRD, and those who had higher HRD scores had a higher rate of pCR at 75%.⁵

More recently, in a phase 2 trial of olaparib monotherapy (NCT03344965), patients with germline mutations were put into cohort 1 and patients with somatic mutations were put into cohort 2. Responses were seen in 5 out of 10 patients with TNBC included in the trial. The overall response rate was 33% in cohort 1 and 31% in cohort 2.⁶

“If we find somatic mutations in BRCA1 and BRCA2, there is some evidence that giving a PARP inhibitor may help with responses in a third of the patients.”

Tumors that are BRCA-like will have high HRD scores, according to Kaklamani. The primary end point of the SWOG S1416 trial (NCT02595905) was PFS in 3 prespecified groups: germline BRCA, BRCA-like, and non–BRCA-like.⁷

Patients with metastatic and/or locoregionally recurrent TNBC or germline BRCA1/2 mutationassociated HER2-negative metastatic breast cancer were tested for mutations after 1:1 randomization. To be in the BRCA-like group, they had to have an HRD genomic instability score of 42 or more, a somatic BRCA1/2 mutation, BRCA1 promoter methylation, or mutations in germline homologous recombination repair genes besides BRCA1/2.

Investigators assessed the efficacy of oral veliparib at 300 mg twice a day on days 1 through 14 plus cisplatin at 75 mg/m² on day 1 of a 21-day cycle compared with cisplatin and placebo.

In the germline BRCA and non–BRCA-like groups, there was no statistically significant difference between veliparib and placebo for the median PFS or overall survival. Conversely, in the BRCA-like group, patients experienced a better median PFS with veliparib at 5.9 months versus 4.2 months with placebo, which reached statistical significance (HR, 0.53; 95% CI, 0.340.83; P = .006) (TABLE).⁷

The overall response rate for this group (n = 83) was 45% with veliparib and 33% with placebo, “showing that [the] veliparib and cisplatin combination can be effective in BRCA-like tumors…. We don’t want to be using a PARP inhibitor in non–BRCA-like or BRCA-mutated patients,” Kaklamani explained.

Upcoming in this setting is the phase 2 PERSEVERE study (NCT02101385) for patients with TNBC and residual disease after neoadjuvant therapy to analyze the use of genomically directed therapy. Patients will be separated according to whether they are positive or negative for genomically directed mutations through circulating tumor DNA (ctDNA). If their ctDNA comes back negative, they will be given physician’s choice of treatment. If it comes back positive but there is no genomic target, they will be given the standard of care.

If a patient’s ctDNA comes back positive and they have a genomically directed pathway, they will be given 1 of 4 therapies. These include a PARP inhibitor for the DNA repair pathways, atezolizumab for alterations in the immunotherapy pathways, ipatasertib for the PI3K/ AKT/mTOR pathways, and a PARP inhibitor plus atezolizumab for the DNA repair plus immunotherapy pathways. All of these therapies are in combination with capecitabine.

“This tells [us] that, if this trial is successful, we will be able to use the patient’s tumor’s mutations to target their treatment instead of giving every single patient the exact same chemotherapy, which is what we’ve been doing so far,” Kaklamani said.

_References:

_{1. Kaklamani V. Genomic tools that predict response in breast cancer. Presented at: 22nd Annual Lynn Sage Breast Cancer Symposium; September 10-12, 2020; Virtual. Accessed September 23, 2020. https:// bit.ly/2SgTtT6}

_{2. Kim SB, Dent R, Im SA, et al; LOTUS investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18(10):1360-1372. doi:10.1016/S1470-2045(17)30450-3}

_{3. Schmid P, Abraham J, Chan S, et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple- negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38(5):423-433. doi:10.1200/JCO.19.00368}

_{4. Telli ML, McMillan A, Ford JM, et al. Homologous recombination def iciency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): a pooled analysis. Cancer Res. 2016;76(suppl 4):P3-07-12. doi:10.1158/1538-7445.SABCS15-P3-07-12}

_{5. Kaklamani VG, Jeruss JS, Hughes E, et al. Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). Breast Cancer Res Treat. 2015;151(3):629638. doi:10.1007/s10549-015-3435-y}

_{6. Tung NM, Robson ME, Ventz S, et al; Translational Breast Cancer Research Consortium. TBCRC 048: a phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded). J Clin Oncol. 2020;38(suppl 15):1002. doi:10.1200/JCO.2020.38.15_ suppl.1002}

_{7. Sharma P, Rodler E, Barlow WE, et al. Results of a phase II randomized trial of cisplatin +/- veliparib in metastatic triple-negative breast cancer (TNBC) and/or germline BRCA-associated breast cancer (SWOG S1416). J Clin Oncol. 2020;38(suppl 15):1001. doi:10.1200/JCO.2020.38.15_ suppl.1001}