Lajos Pusztai, MD

Lajos Pusztai, MD, DPhil, professor of medicine and coleader of Genetics, Genomics, and Epigenetics at Yale Cancer Center, discusses the promise of neoadjuvant immunotherapy trials including the KEYNOTE-522 trial (NCT03036488) evaluating pembrolizumab (Keytruda) plus chemotherapy in patients with triple-negative breast cancer (TNBC).

Pusztai says that the introduction of immune checkpoint inhibitors (ICIs) enabled investigators to study whether a greater immune response with more immune cells present in the tumor microenvironment improves the overall prognosis of patients with TNBC.

There have been several trials that have explored preoperative ICI therapy in TNBC, showing an increase in pathologic complete response (pCR) rate, with the exception of the NeoTRIPaPDL1 study (NCT002620280) of atezolizumab (Tecentriq). While the pCR increase in these trials is not numerically high, it has shown statistical significance in larger trials. Event-free survival (EFS) benefit may be seen 

According to Pusztai, the GeparNuevo trial (NCT02685059) results reported in August 2022 showed an absolute increase of 9 percentage points in pCR rate in 88 patients who were randomly assigned to receive durvalumab (Imfinzi) with neoadjuvant chemotherapy versus 86 who received chemotherapy alone. In KEYNOTE-522, in which over 1000 patients were enrolled, pembrolizumab had a 13.6 percentage point absolute increase in pCR versus chemotherapy and a strong EFS advantage, supporting the use of neoadjuvant ICI therapy for TNBC.

 The advent of immunotherapy drugs being highly effective ICIs enabled us to ask this question. If the immune response contributes to the good prognosis, then boosting the immune system will improve the prognosis of patients who have a moderate amount or even large amount of immune cells, you can make that progress better. This was the theoretical background to testing immune checkpoint inhibitors in breast cancer, and lo and behold, it's worked.

 There are at least 4 randomized neoadjuvant chemotherapy trials that tested various different types of ICIs combined with chemotherapy in the preoperative setting. Essentially, all of them showed an improvement in pCR rate, except 1 study in Italy, the NeoTRIP [study] of ​​atezolizumab. We also learned that the pCR rate improvements are relatively modest and often in single digits. In large studies, these reached significance. In smaller phase 2 studies, they did not have significance, just the numerical improvement.

 Even in a relatively small phase 2 trial, GeparNuevo, which tested durvalumab [Imfinzi] under a similar sort of schema of neoadjuvant weekly nab-paclitaxel followed by EC [epirubicin plus cyclophosphamide] with or without durvalumab, showed a slight improvement in pCR rate and a significant improvement in EFS. I think the data are very consistent that ICIs improve the outcome of patients with triple-negative disease. KEYNOTE-522 is the largest and most definitive study.

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Lajos Pusztai, MD, DPhil, discusses the promise of neoadjuvant immunotherapy trials including the KEYNOTE-522 trial evaluating pembrolizumab plus chemotherapy in patients with triple-negative breast cancer.

Background for Neoadjuvant Immunotherapy Improving TNBC Prognosis

Lajos Pusztai, MD, DPhil, professor of medicine and coleader of Genetics, Genomics, and Epigenetics at Yale Cancer Center, discusses key takeaways from analysis of the KEYNOTE-522 (NCT03036488) clinical trial of pembrolizumab (Keytruda) plus chemotherapy in the neoadjuvant or adjuvant setting for patients with triple-negative breast cancer (TNBC).

The phase 3 KEYNOTE-522 study randomly assigned patients with stage II or III TNBC 2:1 to receive neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by definitive surgery, then adjuvant pembrolizumab or placebo.

Pusztai says that the pembrolizumab benefited patients who had a pathologic complete response (pCR) but also appeared to benefit many who had a worse response to treatment based on their event-free survival (EFS).

Those with residual cancer burden scores of 2 (RCB2) which were the largest subpopulation that did not have a complete response, had a 3-year EFS rate of 75% with pembrolizumab versus 56% with chemotherapy alone, translating to an improvement in reduction of risk of local or distant recurrence, progression, or death. According to Pusztai, the greatest difference in the arms was a reduced risk of distant metastatic recurrence with pembrolizumab.

 The most important finding from my presentation is that the benefit from pembrolizumab extended beyond just increasing the pCR rates. Many patients who did not achieve pCR also benefited from pembrolizumab. We see this by plotting their EFS by the various residual disease categories for those who had less than a complete response. The largest statistically clearly significant benefit was seen among those who are in the RCB2 category, which happens to be the largest subpopulation among those who do not achieve a complete response.

That was approximately 20% of the entire study population on the pembrolizumab arm and the chemotherapy alone arm combined that had this RCB2 extent of residual disease. If they were randomized to the pembrolizumab arm, the EFS at 3 years was 75% compared to only 56% in those who only received chemotherapy with the placebo. That's almost a 20% improvement in EFS. This means that we avoided in 20% of the patients, either local recurrence, distant recurrence, or progression [or death] during the neoadjuvant phase. In fact, the events that pembrolizumab prevented most were distant metastatic recurrences.

Lajos Pusztai, MD, DPhil, discusses key takeaways from analysis of the KEYNOTE-522 clinical trial of pembrolizumab plus chemotherapy in the neoadjuvant or adjuvant setting for patients with triple-negative breast cancer.

Pembrolizumab Shows EFS Benefit in TNBC Without Complete Response

Lajos Pusztai, MD, DPhil, professor of Medicine (Medical Oncology), and co-leader of Genetics, Genomics, and Epigenetics at Yale Cancer Center, discusses multiple analyses of the phase 3 KEYNOTE-522 (NCT03036488) clinical trial of pembrolizumab (Keytruda) plus chemotherapy administered in the neoadjuvant or adjuvant setting to patients with triple-negative breast cancer (TNBC) versus placebo plus chemotherapy.

In prior analyses of KEYNOTE-522, pembrolizumab demonstrated pathologic complete responses in the first 603 patients out of 1174, meeting 1 of its primary end points. In comparison with chemotherapy alone, the pCR improvement was approximately 13%, according to Pusztai.

The second primary end point of event-free survival was also met during an interim analysis. Eight-five percent of patients in the pembrolizumab had EFS events compared with 77% in the placebo arm.

During the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, updated findings presented by Pusztai showed that an increased residual cancer burden (RCB) score correlated with worse EFS in patients with TNBC, however, there was an EFS improvement with pembrolizumab/chemotherapy vs the control arm in patients with lower RCB scores.

 KEYNOTE-522 is the largest neoadjuvant/adjuvant trial via immune checkpoint inhibitor in triple-negative breast cancer. The trial design included approximately 20 to 24 weeks of neoadjuvant chemotherapy with weekly taxol followed by regular adriamycin/ cyclophosphamide, or epirubicin/cyclophosphamide chemotherapy, either without or with every 3-week pembrolizumab.

 And after surgery patients continued with pembrolizumab or a placebo. So, this was a double-blind, placebo-controlled, phase 3, randomized trial that included overall 1174 patients. The primary endpoints included both pathologic complete response rate during the neoadjuvant phase and event-free survival in the combined neoadjuvant followed by adjuvant phases of the study. And the preplanned first primary outcome analysis was done after the first 602 patients had pathological complete response.

 The study has met its primary endpoint. For this outcome, it showed a pathological complete response rate improvement of approximately 13% compared to chemotherapy alone. And subsequently, in the fourth interim analysis, which was again a preplanned statistical analysis, the second primary end point [of] event-free survival was also met. Overall, 85% or close to 85% of the patients in the pembrolizumab arm were event free compared to 77% in the placebo arm. Again, this represents about 8% improvement in event-free survival.

 So, what I presented at the ASCO was the updated results now including pathological complete response rates and the distribution of residual cancer burden in the entire study population. It also showed the event-free survival by residual disease categories.

Pusztai L, Denkert C, O'Shaughnessy J, et al. Event-free survival by residual cancer burden after neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy for early TNBC: Exploratory analysis from KEYNOTE-522. J Clin Oncol. 2022; 40 (suppl 16; abstr 503). doi: 10.1200/JCO.2022.40.16_suppl.503

Lajos Pusztai, MD, DPhil, discusses multiple analyses of the phase 3 KEYNOTE-522 clinical trial of pembrolizumab plus chemotherapy administered in the neoadjuvant or adjuvant setting to patients with triple-negative breast cancer versus placebo plus chemotherapy.

Efficacy of Neoadjuvant/Adjuvant Pembrolizumab in TNBC

Lajos Pusztai, MD, professor of medicine, chief of Breast Medical Oncology, Yale Cancer Center, and Co-Director, Yale Cancer Center Genetics, Genomics and Epigenetics Program, discusses the potential role of immunotherapy in the management of breast cancer.

Lajos Pusztai, MD | Authors

Articles

Background for Neoadjuvant Immunotherapy Improving TNBC Prognosis

Pembrolizumab Shows EFS Benefit in TNBC Without Complete Response

Efficacy of Neoadjuvant/Adjuvant Pembrolizumab in TNBC

The Potential Role of Immunotherapy in the Management of Breast Cancer