KEYNOTE-522 final data boost pembrolizumab role in early breast cancer

Results from the phase III KEYNOTE-522 study presented at ESMO 2024 show a statistically significant and clinically meaningful improvement in overall survival (OS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemo alone for previously untreated, high-risk, early-stage triple-negative breast cancer (TNBC).

After a median follow-up of 75.1 months, 14.7 percent of participants in the pembrolizumab arm had died. In the control arm, the corresponding rate was 21.8 percent. A comparison between arms yielded a hazard ratio (HR) of 0.66 (p=0.0015). “The prespecified significance boundary of 0.00503 was met,” noted Professor Peter Schmid from Barts Cancer Institute, Queen Mary University, London, UK, at ESMO 2024.

The 5-year OS rates in the pembrolizumab and control arms were 86.6 percent and 81.7 percent, respectively. For event-free survival (EFS) at 5 years, the rates were 81.2 percent and 72.2 percent, respectively (HR, 0.65). [ESMO 2024, abstract LBA4]

The OS benefit in the pembrolizumab arm was relatively consistent across prespecified subgroups, irrespective of PD-L1 expression (HRs, 0.70 and 0.51 for CPS* ≥1 and <1, respectively), nodal status (HRs, 0.65 for both positive and negative), and tumour size (HRs, 0.51 and 0.88 for T1/T2 and T3/T4).

Looking at the OS by pathologic complete response (pCR), the pembrolizumab-based regimen appeared to do better among those who had no pCR or did not have an optimal response to the regimen, noted Schmid. “There was still a substantially better outcome in terms of OS rates [with pembrolizumab], with a 6-percent difference at 5 years (71.8 percent [pembrolizumab] vs 65.7 percent [control]; HR, 0.76).”

“Among those who had pCR, the events seem to occur slightly later (95.1 percent vs 94.4 percent, respectively; HR, 0.69). We have yet to see whether the curves will eventually [separate],” he continued.

The incidences of grade ≥3 treatment-related adverse events (AEs) were similar between the pembrolizumab and control arms (77.1 percent and 73.3 percent), but the former had a higher percentage of any-grade immune-mediated AEs (35 percent vs 13.1 percent).

“Nonetheless, with longer follow-up, the toxicity profile remained consistent with the previous analyses and established safety profiles of pembrolizumab and chemo. We did not observe any new safety concerns,” said Schmid.

A new SoC?

A total of 1,174 participants (median age 48 years) were randomized 2:1 to receive neoadjuvant pembrolizumab 200 mg Q3W or placebo, with four cycles of paclitaxel plus carboplatin**, then four cycles of doxorubicin or epirubicin plus cyclophosphamide***. Following definitive surgery, participants were given adjuvant pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity.

KEYNOTE-522 has met its dual primary endpoints, showing statistically significant and clinically meaningful improvements in pCR and EFS with neoadjuvant pembrolizumab-chemo + adjuvant pembrolizumab in this patient setting. [N Engl J Med 2020;382:810-821; N Engl J Med 2022;386:556–567]

“Based on this study, regulatory authorities worldwide have approved pembrolizumab in combination with chemo as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery for stage II-III TNBC, and this regimen is now in most of the up-to-date clinical guidelines,” said Schmid.

“[The current results after a median follow-up of over 6 years] provide further support for pembrolizumab plus platinum-containing chemo before surgery followed by pembrolizumab after surgery as a standard-of-care (SoC) treatment regimen for patients with high-risk, early-stage TNBC,” he added.

Practice-changing data

The addition of pembrolizumab to chemo has led to more patients achieving pCR, which has been previously presented, noted discussant Dr Marleen Kok from the Netherlands Cancer Institute, Amsterdam, the Netherlands, at ESMO 2024. “In today’s presentation, we’ve seen that pembrolizumab contributes to the cure of TNBC patients … Moreover, the non-pCR group seems to benefit [more from the regimen,] and that is extremely important.”

“[Although] the information fraction states that only 67 percent of events were reached in this interim analysis, I do not think that is a concern given the very long follow-up of over 6 years,” Kok stressed.

She further underscored that the industry, academia, and regulatory and guideline committees have a shared responsibility to ensure patients receive the most comprehensive information to guide decisions, minimize overtreatment, and avoid undertreatment.

“We need biomarkers, and we have to limit trials wherein we have no clue as to the contribution of components,” Kok said. “Lastly, we need special attention on long-term immunotherapy toxicity now that we are curing young breast cancer patients with immunotherapy.”

May transform treatment landscape

“The final OS data … represent some of the most significant results observed in the treatment of early breast cancer,” commented Dr Carmen Criscitiello from the European Institute of Oncology, Milan, Italy, during the Presidential Symposium at ESMO 2024.

“The results confirm the potential of pembrolizumab as a key component of combination treatment regimens for high-risk, early-stage TNBC, and pembrolizumab plus chemo should be considered a new SoC in this setting,” Criscitiello continued.

She added that these data are particularly relevant as TNBC is a subtype with poor prognosis and few treatment alternatives and that incorporating immunotherapy into the earlier stages of treatment may transform the management of these patients.

Criscitiello noted that the 5-year EFS in the control arm implies that many patients fare well with chemo alone. “We therefore need to be able to identify which patients are likely to have a favourable prognosis without immunotherapy [to] avoid immune-related toxicity in these patients.”

She also emphasized the importance of monitoring longer-term safety and understanding the risk-benefit profile of this regimen to ascertain its overall value in the long term.