Despite Setbacks, pCR Still Acceptable for Breast Cancer Approvals

Gunter von Minckwitz, MD, PhD

Pathologic complete response (pCR) may still have a role in accelerated neoadjuvant approvals for select patients with early stage breast cancer, despite the fact that it remains an unproven surrogate endpoint, according to Gunter von Minckwitz, MD, PhD, during a presentation at the 2016 Miami Breast Cancer Conference.

“The current conditional approval pathway, especially if it is targeting drugs with low-risk profiles, might be an acceptable one. Even with unclear long-term benefits, it is reasonable to go this way,” said von Minckwitz, from the German Breast Group, in University of Frankfurt.

There are benefits associated with the use of pCR as an endpoint for drug approvals, specifically earlier access to promising compounds with new mechanisms of action, noted von Minckwitz. However, there are risks associated with its use, such as a lack of long-term efficacy and toxicity.

“This goes beyond the traditional endpoints of survival, progression-free survival, disease-free survival, and sometimes overall response. To go to a new endpoint–pathologic complete response–is risky,” said von Minchwitz. “The intention is to focus specifically on certain high efficacious agents, with preferably a new mode of action. This is not intended for the traditional cytotoxic agents, but rather to use this pathway for very innovative biologic agents.”

The first agent to gain approval for patients with early-stage breast cancer based on pCR as a surrogate endpoint was pertuzumab (Perjeta). This agent was granted an accelerated approval in late September 2013 in combination with trastuzumab (Herceptin) and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer.

“With the first example of pertuzumab, we can speculate that patients with early breast cancer got access to this innovative compound probably 3 to 4 years earlier compared with the usual pathway,” said von Minckwitz.

In the pivotal data that led to the approval, the pCR rate with the pertuzumab triplet was 39.3% versus 21.5% with trastuzumab and docetaxel alone (P = .0063).¹ In this study, the magnitude of benefit for patients was lower in those with HR-positive tumors compared with the HR-negative subtype.

While a clear connection could not be demonstrated between pCR and long-term outcomes, it was instrumental in the FDA approval of pertuzumab; however, this accelerated approval was not based solely on data from the neoadjuvant setting, von Minckwitz noted. “We had extraordinary efficacy in the metastatic setting, it has a very favorable toxicity profile, and it has no detrimental impact on the relative dose intensity of the backbone treatment,” he noted.

In the metastatic setting, the phase III CLEOPATRA study showed an unprecedented 15.7-month improvement in overall survival (OS) with the combination of pertuzumab, trastuzumab, and docetaxel compared with trastuzumab and docetaxel alone.² In the pertuzumab arm the median OS was 56.5 versus 40.8 months in the control arm (HR, 0.68; 95% CI, 0.56-0.84; P <.001).

To confirm the neoadjuvant approval, the phase III APHINITY trial is currently exploring pertuzumab, trastuzumab, and chemotherapy as an adjuvant therapy for women with HER2-positive breast cancer. This trial has fully accrued 4805 patients for a year of treatment with the triplet compared with the trastuzumab and chemotherapy alone. The estimated study completion date is December 2023 (NCT01358877).

“The APHINITY trial, the adjuvant trial, is fully recruited, so it fits nicely with the two trial approach that was proposed by the FDA,” said von Minckwitz. “The surrogacy of pCR is best shown for trastuzumab, and therefore there is the belief that pertuzumab behaves quite similar, so the risk-benefit ratio is quite favorable."

Although it can be used to expedite approvals, pCR is not meant to support a full FDA indication. Instead, pCR represents an intermediate endpoint, which is a surrogate marker of treatment efficacy assessed earlier than the true outcome of interest, von Minckwitz noted. This type of endpoint is positioned in the middle of a causal sequence of events.

In the phase III NOAH trial,³ pCR was associated with EFS at 5 years in patients who received chemotherapy plus trastuzumab versus chemotherapy alone (HR, 0.29). A pCR was achieved by 45 patients in the trastuzumab arm versus 23 in the chemotherapy alone arm. The 5-year EFS rates were 58% and 43%, with and without trastuzumab, respectively (HR, 0.64; P = .016).

“This fits with the large adjuvant studies that were published later on,” said von Minckwitz. “Here, with an antibody treatment, it seems to work quite well, and therefore there was a feeling that maybe pCR surrogacy is much better present when we use antibody treatments and targeted agents.”

However, this was not the case between the NeoALTTO and ALTTO studies, which explored lapatinib and trastuzumab. These large studies both failed to show a connection between improvements in pCR and survival but did further confirm that patients who achieved a pCR had better long-term outcomes.

“NeoALTTO was probably over optimistic, several other neoadjuvant lapatinib studies are negative,” said von Minckwitz. “On the other hand, ALTTO was probably underpowered. It was a time driven analysis performed with only two-thirds of the required events.”

As it stands now, it is unclear whether pCR will still be instrumental in the approval of other neoadjuvant therapies for breast cancer. The next potential milestone decision could be based off the phase III BRIGHTNESS trial, believes von Minckwitz. This trial is exploring the PARP inhibitor veliparib (ABT-888) as a neoadjuvant therapy for triple-negative breast cancer.

In the 3-arm BRIGHTNESS trial, veliparib, carboplatin, and paclitaxel are being compared with placebo plus carboplatin and paclitaxel or paclitaxel alone. The primary endpoint is pCR, with secondary endpoints focused on eligibility for breast conservation after therapy, survival, and quality of life. The study plans to enroll 624 patients with an estimated completion date of February 2017 (NCT02032277).

1. Gianni L, Pienkowski T, Im Y-H, et al. Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P). J Clin Oncol. 2015;33 (suppl; abstr 505).
2. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-734.
3. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014;15(6):640—647.

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