Neoadjuvant Therapy Impresses in I-SPY 2 Trial for Breast Cancer

Lajos Pusztai, MD, DPhil

Adding the PD-L1 inhibitor durvalumab (Imfinzi) and the PARP inhibitor olaparib (Lynparza) to treatment with neoadjuvant paclitaxel led to better pathologic complete response (pCR) rates in patients with high-risk, HER2-negative stage II/III breast cancer compared with paclitaxel alone, according to investigators on the phase 2 I-SPY 2 study (NCT01042379). The findings were presented at the 2020 Annual American Association for Cancer Research Virtual Meeting.¹

Data showed that in all patients with HER2-negative breast cancer, the predicted probability of pCR with the combination compared with sin-gle-agent paclitaxel was 37% (95% CI, 27%-47%) and 22% (95% CI, 16%-25%), respectively. When broken down by subset, the respective pCR rates were 28% (95% CI, 08%-38%) versus 14% (95% CI, 09%-19%) in patients with hormone receptor (HR)–positive disease. In those with triple-negative breast cancer (TNBC), the pCR rate was 47% (95% CI, 29%-64%) with the combination and 27% (95% CI, 20%-34%) with chemotherapy alone (FIGURE).¹

Moreover, there were no unexpected safety signals; the adverse effects (AEs) were consistent with the known safety profiles of each agent alone.“Durvalumab and olaparib [given] concurrently with paclitaxel increased pCR rates in all 3 biomarker subsets where it was studied,” lead study author Lajos Pusztai, MD, DPhil, professor of medicine (medical oncology) and coleader of genetics, genomics, and epigenetics at Yale Cancer Center in New Haven, Connecticut, said in a virtual presentation during the meeting. “The estimated probability that the experimental arm is superior to chemotherapy alone is greater than 98% in all subsets.”

The rationale to combine checkpoint and PARP inhibition is biologic, Pusztai said, explaining that impaired nucleotide and base excision repair increase mutation and neoantigen load, and DNA fragments activate the intracellular STING pathway. Also, PARP inhibition upregulates PD-L1 expression in breast cell lines.

Previously, results of the open-label phase 1/2 bas-ket MEDIOLA (NCT02734004) trial showed that the combination of olaparib and durvalumab had clinical activity in a cohort of patients with germline BRCA-mutated metastatic breast cancer.² The objective response rate was 63.3% with the combination in this patient population. Another phase 2 trial (NCT03801369) of olaparib and durvalumab in patients with BRCA wild-type metastatic TNBC is ongoing.

I-SPY 2 is an ongoing multicenter, neoadjuvant study that uses response-adaptive randomization with multiple concurrent experimental arms and a shared control arm. Overall, the design is based on Bayesian predictive probability that a biological regimen will be shown to be statistically superior to standard treatment in an equally randomized 300-patient confirmatory trial.³ Regimens that demonstrate a high Bayesian predictive probability of showing superiority in at least 1 of 10 predefined signatures graduate from the I-SPY 2 study.

Regimens are dropped for futility if they show a low predictive probability of showing superiority over standard therapy in all 10 signatures. Up to 120 patients can be assigned to each experimental regimen.

For this arm of I-SPY 2, investigators sought to determine whether the neoadjuvant combination of olaparib, durvalumab, and paclitaxel would increase pCR rates compared with chemotherapy alone in HER2-negative biomarker subgroups of patients with stage II/III breast cancer. The biomarker subsets included all patients with HER2-negative breast cancer, including those with HR-positive, HER2-negative disease and TNBC.

To be eligible, patients must have had a tumor size of at least 2.5 cm, adequate organ function, and an ECOG performance status of less than 2, as well as agree to undergo MRI and biopsy. If patients had HR-positive disease, they needed to have a high MammaPrint score.

Patients received either paclitaxel alone at 80 mg/m2 weekly for 12 cycles (n = 299) or combined with 1500 mg of durvalumab every 4 weeks for 3 cycles, plus olaparib at 100 mg twice daily for weeks 1 to 11 (n = 73). Prior to surgery, all patients received doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/ m2 for 4 cycles, given every 2 or every 3 weeks.

The primary end point of the trial is pCR; gradby RCB-I (minimal burden), RCB-II (moderate burden), and RCB-III (extensive burden) “Durvalumab and olaparib not only increased the rate of pCR, it also shifted RCB categories toward lower values,” Pusztai said. “In other words, there were also fewer RCB-II and RCBIII patients in the experimental arm, indicating smaller residual cancers across the entire residual disease spectrum.” associated with higher pCR rates across both arms, and there was no significant marker-treatment interaction. Furthermore, in the HR-positive/HER2-negative subtype, patients with an ultrahigh MammaPrint score (MP2; n = 77) was found to have the most benefit from the combination, with an estimated pCR rate of 64% compared with 22% in the control arm. In patients with an MP1 score (n = 132), the estimated pCR rate was 9% with olaparib/ durvalumab versus 10% in the control arm. uation was based on the pCR rate for patients who underwent surgery and MRI response over time for those still on treatment. Investigators determined that for the combination regimen to be studied in a future phase 3 trial, the graduation for efficacy was an 85% or greater predicted probability of success with the combination over standard therapy. If the probability of success dropped below 10%, the trial was stopped for futility. The maximum accrual reached was 75 patients overall with HER2-negative breast cancer.

The median age of enrolled patients was 47 years; 79.5% were white, 12% were African American, 7.5% were Asian, and 0.5% were reported as other. Additionally, 62% of patients had HR-positive disease and 38% had HR-negative disease; specifically, in the combination arm, 71% and 29% of patients had HR-positive and HR-negative disease, respectively. The median tumor size was similar between the combination and control arms, at 3.7 cm and 3.8 cm, respectively. Overall, 32.5% of patients had palpable nodes.

Additional results also demonstrated the probability that the experimental regimen was superior to the control arm and the predicted probability of success in a 300-patient randomized trial. In all patients with HER2-negative breast cancer, the probability that olaparib/durvalumab plus chemotherapy was superior to the control arm was 99.9%, and the probability of success in a phase 3 trial was 81.4%.

In the TNBC subset, the probability rate that the combination was superior to the control arm was 98.4%, with an 80.6% rate that it will be successful in a phase 3 study. Finally, in the HR-positive/ HER2-negative group, the probability of success versus that of the control arm was 99.6%; the rate of succeeding in a phase 3 trial was 74.5%.

Moreover, the combination was found to: reduce values of residual cancer burden (RCB) across subtypes except RCB-III in patients with TNBC. RCB is categorized by RCB-I (minimal burden), RCB-II (moderate burden), and RCB-III (extensive burden).

“Durvalumab and olaparib not only increased the rate of pCR, it also shifted RCB categories toward lower values,” Pusztai said. “In other words, there were also fewer RCB-II and RCBIII patients in the experimental arm, indicating smaller residual cancers across the entire residual disease spectrum.”

Regarding safety, AEs were reported in 43 patients in the durvalumab/olaparib arm compared with 251 who received chemotherapy alone, as of March 15, 2020. The rate of grade 3/4 AEs occurred in 58% and 41% of patients in the experimental and control arms, respectively. The most frequent grade 3/4 AEs experienced in the combination arm and the paclitaxel-alone arm, respectively, included febrile neutropenia (16.3% vs 8.4%), colitis (7% vs 0.4%), adrenal insufficiency (7% vs 0%), increase in alanine aminotransferase levels (4.7% vs 2%), dehydration (4.7% vs 0.8%), and vaginal infection (4.7% vs 0%).

Immune-related AEs of special interest also occurred. Nineteen percent of patients receiving durvalumab/olaparib versus 1.6% of those on the chemotherapy-alone arm experienced grade 3 immune-related AEs, including colitis (n = 3), adrenal insufficiency (n = 3), pancreatitis (n =1), and thyroiditis (n = 1).

When exploring prespecified predictive markers, investigators also noted that higher expression of most immune markers was associated with higher pCR rates across both arms, and there was no significant marker-treatment interaction. Furthermore, in the HR-positive/HER2-negative subtype, patients with an ultrahigh MammaPrint score (MP2; n = 77) was found to have the most benefit from the combination, with an estimated pCR rate of 64% compared with 22% in the control arm. In patients with an MP1 score (n = 132), the estimated pCR rate was 9% with olaparib/ durvalumab versus 10% in the control arm.

In the TNBC subset, low CD3/CD8 gene signature ratio, high macrophage/T-cell–major histocompatibility complex class II ratio, and high proliferation signatures were associated with a higher pCR in the combination arm versus the control arm.

As a discussant during the presentation, Pamela Munster, MD, a professor in the Department of Medicine (Hematology/Oncology) at the University of California, San Francisco (UCSF), and director of the Early Phase Clinical Trials Unit, coleader of the Center for BRCA Research, and leader of the Experimental Therapeutics Program at UCSF Helen Diller Family Comprehensive Cancer Center, shared her insight on where this combination may fit best for this patient population.

“What we know so far in preoperative therapy for breast cancer is that pCR is associated with better outcomes,” Munster said. “What we learned from Dr. Pusztai’s presentation is that there may be promising activity with olaparib and durvalumab in addition to paclitaxel. This combination may be of particular interest to a subgroup of women with tumors expressing ultra-high MammaPrint. The toxicity, as presented today, appears incomplete, and one should consider the financial toxicity from this combination.”

_References:

_{1. Pusztai L, Han HS, Yau C, et al. Durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/ III breast cancer: results from the I-SPY 2 trial. Presented at: 2020 American Association for Cancer Research Annual Virtual Meeting; April 27-28, 2020. Abstract CT011. https://bit.ly/3cdK2fK}

_{2. Domchek S, Postel-Vinay S, Im S, et al. Phase II study of olaparib (O) and durvalumab (D) (MEDIOLA): updated results in patients (pts) with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Ann Oncol. 2019;30(suppl 5):v477. doi:10.1093/annonc/mdz253.017}

_{3. I-SPY2 trial demonstrates significant improvement in pCR with durvalumab and olaparib with paclitaxel, (compared to cheER, estrogen receptor; pCR, pathologic complete response; TNBC, triple-negative breast cancer. motherapy alone) in women with stage II/III high-risk, HER2-negative breast cancer, in HR+ and TNBC subsets [news release]. News release. Quantum Leap Healthcare Collaborative. April 27, 2020. Accessed April 27, 2020. prn.to/2yKj3cT}