Part 1: Insights from ESMO 2019 – Focus on Immunotherapy

Checkmate-227 data in 1L NSCLC

New data have shown that first-line (1L) treatment with a combination of nivolumab and ipilimumab improves overall survival in a subset of patients with advanced non-small cell lung cancer (NSCLC) compared to chemotherapy. The data from the CheckMate-227 trial, showed that the combination of nivolumab plus low-dose ipilimumab could offer a chemotherapy-free option for 1L treatment of patients with advanced NSCLC.

One of the limitations of the study was that the observed OS benefit was compared to chemo alone, while the current standard of care is now chemo/pembro in most of these patients based on the significant survival benefit seen in the KEYNOTE-189 and KEYNOTE-407 trials for patients with advanced non-squamous and squamous NSCLC, respectively. While the non-chemotherapy regimen may appeal to some patients and oncologists, the uptake of the regimen may be muted, similar to the market uptake in metastatic melanoma, where both nivo/ipi are approved as well. The significant toxicity has prevented the uptake of the regimen for most metastatic melanoma patients. Therefore, it is likely that that the nivo/ipi combo may have an uphill battle in gaining share in 1L NSCLC compared to other recommended treatment options.

Adding Pembrolizumab to Neoadjuvant Chemotherapy Improves Outcome in Early TNBC

The addition of pembrolizumab to standard neoadjuvant chemotherapy provided greater rates of pathological complete response (pCR) in patients with early triple negative breast cancer (TNBC), according to findings from the phase III KEYNOTE-522 trial.

Prior studies, including the Phase Ib KEYNOTE-173 and phase II I-SPY 2 clinical trials demonstrated promising anti-tumor activity and a manageable safety profile with neoadjuvant pembro in combination with chemotherapy in patients with early TNBC. Therefore, the KEYNOTE-522 study evaluated neoadjuvant pembro plus chemotherapy followed by adjuvant pembro to further characterize the efficacy and safety in patients with early stage TNBC. The KEYNOTE-522 study showed greater anti-tumor activity of pembro plus chemotherapy observed regardless of PD-L1 status.

Analysis of data based on PD-L1 status showed that pCR defined as ypT0/Tis ypN0 was higher with the pembrolizumab regimen in both the PD-L1-positive and PD-L1-negative subgroups. The pCR rates were 68.9% versus 54.9% in the PD-L1-positive cohort and 45.3% versus 30.3% in the PD-L1-negative population in patients receiving chemotherapy plus pembrolizumab or placebo, respectively.

Patients treated with neoadjuvant pembro plus chemotherapy followed by adjuvant pembro also showed a favorable trend in EFS compared to patients on the neoadjuvant placebo plus chemotherapy followed by adjuvant placebo treatment (hazard ratio [HR] 0.63; 95% CI, 0.43-0.93).

Based upon data presented at ESMO 2019 Congress the investigators were able to conclude that pembro plus chemotherapy as neoadjuvant treatment significantly increased the pCR rate over neoadjuvant chemotherapy plus placebo in patients with early TNBC.

PROMISE trial in pleural mesothelioma

The PROMISE-meso trial (Abstract LBA91_PR) is the first randomized trial to compare pembrolizumab and single-agent chemotherapy (gemcitabine or vinorelbine) in this setting. The negative trial results were a surprise to many at ESMO. Although the overall response rate was significantly higher with pembrolizumab (22% versus 6%, p=0.004) at a median follow-up of 12 months, there was no difference between pembrolizumab and chemotherapy in progression-free survival (median 2.5 months versus 3.4 months; hazard ratio [HR] 1.06; p=0.76) or overall survival (median 10.7 months versus 11.7 months; HR 1.05; p=0.85).

“The results from this trial are disappointing, but perhaps not surprising,” according to Prof. Dean Fennell from Leicester Cancer Research Centre, UK. The study faced two major challenges. First, it compared pembro to active controls —vinorelbine or gemcitabine—both agents are known to be active in relapsed MPM. The other major challenge for the PROMISE-meso trial was that it enrolled an unselected patient population, which could have effectively diluted the magnitude of the pembo benefit. There is likely to be a subgroup of patients, probably characterized by high tumor PD-L1 expression, who will benefit from pembro and this subgroup needs to still be defined.

Immunotherapy-related hyperprogression may represent a further potential complication with the use of checkpoint inhibitors in malignant pleural mesothelioma (MPM). Long-term results of a phase II study in relapsed MPM reported that single-agent nivolumab and a combination of nivolumab plus ipilimumab were associated with median long-term survival rates of 11.9 months and 15.9 months, respectively, with corresponding 2-year survival rates of 25.4% and 31.7% (Abstract 1841O). However, the 11 patients who were identified with hyperprogression measured according to tumor growth kinetics had worse survival (median 2.6 months) than patients with standard progression (median 5.5 months; HR 0.37; p=0.006) or patients with disease control (median 23.1 months; HR 0.12; p<0.0001). It is not clear whether immunotherapy may lead to hyperprogression. The origin of Immunotherapy-induced hyperprogression is still unclear to researchers, but it might be due to disease that is refractory to treatment.

Treatment with immunotherapy and targeted therapy may be the way forward for relapsed MPM. This will involve both looking at different ways of using existing drugs, primarily in selected populations, and also exploring new drugs.

Be sure to check out Part 2 of our Insights from ESMO 2019 series where we will focus on practice changing data in solid tumors.

References

Abstract LBA7128 ‘Nivolumab (nivo) + low-dose ipilimumab (ipi) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate-227 part 1 final analysis’ will be presented by Solange Peters during the Presidential Symposium I on Saturday, 28 September, 16:30 to 18:20 (CEST) in Barcelona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019

LBA8_PR – Schmid P, Cortés J, Dent R, et al. KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC)

LBA91_PR – A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM): Results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial

1841O – Second/third-line nivolumab vs nivo plus ipilimumab in malignant pleural mesothelioma: Long-term results of IFCT-1501 MAPS2 phase IIR trial with a focus on hyperprogression