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Immunochemotherapy

AACR 2019: Pembrolizumab combined with chemotherapy improves survival of patients with NSCLC with brain and liver metastases

With the KEYNOTE-189 study, combined immunochemotherapy became the new first-line standard for metastastatic nonsquamous non-small-cell lung cancer. A recent update of the trial now reveals that patients with brain or liver metastasis benefit as well as patients without metastases.

In September 2018, the first combined immunochemotherapy with the checkpoint inhibitor Pembrolizumab was approved for first line therapy of metastatic non-small-cell lung cancer (NSCLC) with nonsquamous histology independent of PD-L1 status based on results of the phase III clinical trial KEYNOTE-189. In this trial, 616 patients were randomized 2:1 and treated with either pembrolizumab plus platinum-based chemotherapy (cisplatin or carboplatin, plus Pemetrexed), or chemotherapy alone. Published at the AACR 2018 Annual Meeting and in the New England Journal of Medicine, a significant improvement of overall survival (OS; HR: 0,49; p<0,001) and progression-free survival (PFS; HR 0,52; p<0,001) was seen for combined immunochemotherapy compared to chemotherapy alone at a median follow-up of 10.5 months.1,2

At the AACR 2019 Annual Meeting, lead author Dr. Marina Garassino, National Tumor Institute, Milan, Italy, presented an unplanned post-hoc subgroup analysis to evaluate efficacy in patients who had brain or liver metastases at the onset of the study.3

Survival benefit irrespective of liver or brain metastases

Patient characteristics were relatively balanced between study arms. Stable brain metastases were found in 73 of 410 patients (18 percent) in the pembrolizumab/chemotherapy arm, and in 35 of 206 patients (17 percent) in the chemotherapy arm. Liver metastases were more frequent in the chemotherapy comparator arm (24 vs. 16 percent with only chemotherapy).

Patients with liver metastases

In patients with liver metastases, addition of pembrolizumab to chemotherapy improved OS significantly, and reduced hazard of death by 38 percent (HR 0.62) with a median OS benefit of 6 months (12.6 vs. 6.6 months). In the group without liver metastases the hazard of death was reduced by 42 percent (HR 0.58), and median OS was improved by 10.5 months (23.7 vs. 13.2 months). After one year, 51.0 versus 30.6 percent of patients with liver metastases were still alive, compared to 73.6 versus 53.5 percent of patients without liver metastases. Similarly, median PFS in the pembrolizumab group was improved (6.1 vs. 3.4 months), with a reduction of progression risk by 48 percent (HR 0.52). After one year, 27.9 percent of patients in the Pembrolizumab arm were progression-free, versus 12.9 percent in the chemotherapy arm. In the group without liver metastases, median PFS was 9.2 months versus 5.4 months, with a risk reduction by 52 percent (HR 0.48), and with 40.9 versus 17.9 percent of patients who were still progression-free after one year.

Patients with brain metastases

In the group of patients with brain metastases, risk of death was reduced by 59 percent in the pembrolizumab arm (HR 0.41), with a median OS benefit of 11.7 months (19.2 vs. 7.5 months). After one year, 65.4 percent of patients in the Pembrolizumab arm were still alive, versus 34.4 percent in the chemotherapy arm. In patients without brain metastases, HR for death was 0.59 (41 percent risk reduction), with a median OS benefit of 10.3 months (22.4 versus 12.1 months), and a 1-year OS of 71.0 versus 50.9 percent. Pembrolizumab reduced progression risk by 58 percent (with brain metastases) or 52 percent (without brain metastases). The respective median PFS was 6.9 versus 4.7 months with brain metastases, and 9.2 versus 4.9 months without brain metastases. After one year, 31.7 versus 8.6 percent of patients with brain metastases were without disease progression, in the group without brain metastases 40.3 versus 18.5 percent.

No new safety signals

Combined immunochemotherapy with Pembrolizumab was generally well tolerated in patients with and without brain or liver metastases. Safety profile of the two subgroups of patients with liver and brain metastases was in line with published data of the general population. No new or unexpected adverse events were reported.

Conclusion

In the KEYNOTE-189 trial, combined immunochemotherapy with pembrolizumab led to an overall and progression-free survival benefit of patients with liver or brain metastases as well as of patients without metastases, compared to chemotherapy alone. Pembrolizumab combined with cisplatin or carboplatin, plus pemetrexed is the standard therapy for patients with newly diagnosed, metastatic nonsquamous NSCLC.

References:
  1. Gandhi L et al., AACR 2018, oral presentation & abstract #CT075.
  2. Gandhi L et al., N Engl J Med 2018; 378: 207892.
  3. Garassino MC et al., AACR 2019, oral presentation & abstract # CT043.
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