Blogs

The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the International Association for the Study of Lung Cancer (IASLC) World Conference of Lung Cancer (WCLC) 2018 held in Toronto, Canada on Sept. 23-26, 2018.

Atezolizumab plus carboplatin-etoposide improves OS and PFS in patients with extensive-stage SCLC: IMpower133 (PL02.07)

Steven V. Liu, MD (Georgetown University, Washington, DC) presented data from the global Phase 1/3, double-blind, randomized, placebo-controlled IMpower133 trial (NCT02763579), evaluating efficacy and safety of atezolizumab in combination with first-line carboplatin and etoposide in treatment-naive extensive-stage SCLC patients. In all, 403 patients were randomized 1:1 to receive four 21-day cycles of carboplatin and etoposide with atezolizumab (n = 201, 1200 mg IV, Day 1, Q3W) or placebo (n = 202). Median OS was 12.3 months and 10.3 months in the atezolizumab and placebo groups, respectively (HR 0.70 [95% CI: 0.54-0.91, p = 0.0069]). The 1-year OS rate was 51.7% in the atezolizumab group and 38.2% in the placebo group. Median PFS was 5.2 months and 4.3 months, respectively (HR 0.77 [95% CI: 0.62-0.96, p = 0.017]). There was no significant difference in ORR (60.2% vs 64.4%) or in median duration of response (4.2 vs 3.9 months). In an exploratory analysis of survival outcomes in selected patient subgroups, HR crossed 1 for patients with liver and brain metastases. Immune-related AEs were more common with atezolizumab compared with placebo (39.9% vs 24.5%). These data suggest that atezolizumab plus carboplatin-etoposide has potential to be a new standard of care for the first-line treatment of extensive-stage SCLC.

[The link to co-publication - https://www.nejm.org/doi/full/10.1056/NEJMoa1809064]

Pembrolizumab plus chemotherapy provides higher efficacy in metastatic squamous NSCLC patients: KEYNOTE-407 (MA10.08)

Balazs Halmos, MD (Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY) presented data from the randomized, double-blind, Phase III KEYNOTE-407 study (NCT02775435), investigating the potential of pembrolizumab plus chemotherapy with carboplatin and paclitaxel or nab-paclitaxel to prolong the survival of previously-untreated, metastatic squamous NSCLC patients. A total of 559 eligible patients were randomized 1:1 to receive pembrolizumab (n = 278, 200 mg, Q3W) or placebo (n = 281) for up to 31 cycles continued after concomitant use with four 21-day cycles of carboplatin and paclitaxel or nab-paclitaxel. Median OS was 15.9 months and 11.3 months in the pembrolizumab and placebo groups, respectively. Pembrolizumab plus chemotherapy prolonged OS (HR 0.64 [95% CI: 0.49-0.85, p < 0.001]) and PFS (HR 0.56 [95% CI: 0.45-0.70, p < 0.0001]) compared with placebo plus chemotherapy. Grade 3-5 AEs in the pembrolizumab + chemotherapy arm vs placebo + chemotherapy arm was 63.9% vs 59.3% in paclitaxel recipients and 78.9% vs 81.4% in nab-paclitaxel recipients. The most common AEs in both trial groups were anemia, alopecia, and neutropenia. Immune-mediated AEs and infusion reactions occurred in 28.8% of patients in the pembrolizumab-combination group and 8.6% in the placebo-combination group; the events of grade 3 or higher were in 10.8% and 3.2%, respectively. One patient in each group died from an immune-mediated AE (pneumonitis). This study indicates that the addition of pembrolizumab to chemotherapy with carboplatin and a taxane was generally tolerable and prolonged OS and PFS as first-line therapy in previously-untreated patients with metastatic squamous NSCLC regardless of taxane choice.

[The link to co-publication - https://www.nejm.org/doi/full/10.1056/NEJMoa1810865]

Durvalumab prolongs PFS in unresectable, stage III  NSCLC patients without progression after chemoradiotherapy: PACIFIC updates (PL02.01)

Scott J. Antonia, MD, PhD (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL) detailed updated results from the global Phase III, randomized, double-blind, placebo-controlled PACIFIC study (NCT02125461), assessing the effects of durvalumab following concurrent chemoradiotherapy in locally advanced, unresectable NSCLC patients without progression. In all, 713 patients (WHO PS 0/1, ≥ 2 chemoradiation treatments) were randomized 2:1 to receive durvalumab (n = 476, 10 mg/kg IV, Q2W) or placebo (n = 237) for up to 12 months. Durvalumab improved OS (HR 0.68 [99.73% CI: 0.469-0.997, p = 0.00251]) with the median not reached (NR; 95% CI, 34.7 months–NR) vs placebo 28.7 months (95% CI, 22.9–NR). Updated PFS remained similar (HR 0.51 [95% CI: 0.41-0.63]) with medians of 17.2 and 5.6 months with durvalumab and placebo, respectively. Durvalumab improved the updated TTDM (HR 0.53 [95% CI, 0.41-0.68]). In durvalumab and placebo groups, 30.5% and 26.1% had grade 3/4 any-causality AEs; 15.4% and 9.8% discontinued due to AEs. These updated data suggest that durvalumab is well tolerated and provide a survival advantage following chemoradiotherapy in unresectable stage III NSCLC patients.

Addition of atezolizumab to carboplatin/cisplatin + pemetrexed provides a benefit to PFS in patients with stage IV non-squamous NSCLC: IMpower132 (OA05.07)

Vassiliki Papadimitrakopoulou, MD (University of Texas MD Anderson Cancer Center, Houston, TX) presented the latest results from the global, randomized, open-label, Phase III IMpower132 study (NCT02657434), investigating the safety and efficacy of atezolizumab in combination with cisplatin or carboplatin plus pemetrexed in chemotherapy-naïve patients with stage IV non-squamous NSCLC. A total of 578 eligible patients were randomized 1:1 to receive atezolizumab (n = 292, 1200 mg IV, Q3W) + cisplatin/carboplatin + pemetrexed or cisplatin/carboplatin + pemetrexed (n = 286) for four or six 21-day cycles. Atezolizumab plus chemotherapy improved median PFS (7.6 months vs 5.2 months for the control group) associated with 40% reduction in risk for progression (HR 0.60 [95% CI: 0.49-072]) across key clinical subgroups. The interim OS analysis of atezolizumab plus pemetrexed-based chemotherapy indicated a benefit: 4.5 months over pemetrexed-based chemotherapy alone (HR 0.81 [95% CI: 0.64-1.03]). Grade 3-5 treatment-related AEs were identified in 58% of patients with atezolizumab + chemotherapy and 42% with chemotherapy alone. These data suggest that the addition of atezolizumab to a backbone of chemotherapy with carboplatin and pemetrexed supports a positive benefit-risk profile compared to chemotherapy alone.

Durvalumab with first line chemotherapy indicates sufficient efficacy in advanced mesothelioma patients: DREAM (OA08.02)

Anna K. Nowak, MB BS PhD W. Aust., FRACP (University of Western Australia, Australia) described results from the open-label, single-arm Phase II DREAM trial (ACTRN12616001170415), examining the safety, tolerability and efficacy of durvalumab with cisplatin and pemetrexed as first line therapy in malignant pleural mesothelioma. All 54 patients received durvalumab (1125 mg, Q3W), cisplatin and pemetrexed up to 6 cycles, followed by 12 cycles of durvalumab for maintenance. The primary endpoint PFS at 6 months (PFS6) was 57% (90% CI: 45-68), median PFS was 6.2 months (95% CI: 5.5-9.0). ORR was 48% (95% CI: 35-61) according to mRECIST and 50% (95% CI: 37-63) according to iRECIST. The median duration of response was 6.5 months. Grade 3-5 AEs occurred in 36 participants (66%), including neutropenia (13%), nausea (11%), anemia (7%), fatigue (6%) and any grade peripheral neuropathy (35%). Immune-related AEs occurred in 15 participants, and were of grade 3 or worse in 8, including increased lipase, pancreatitis, and renal impairment. These preliminary data suggest that the combination of durvalumab with cisplatin and pemetrexed has demonstrated sufficient activity, safety, and tolerability as first line therapy in malignant pleural mesothelioma to warrant further evaluation in a large-scale, randomized Phase III trial.

Pembrolizumab is effective in previously-treated malignant mesothelioma patients (OA08.03)

Arpita Desai, MD (University of Chicago, Chicago, IL) presented results from a Phase II trial (NCT02399371), assessing the OS rate of pembrolizumab in a non-selected population of malignant mesothelioma patients and determining a PD-L1 expression threshold using the 22C3 antibody. Pembrolizumab (200 mg IV, Q3W) was administered to 64 patients for a median of 8 cycles (range 1-34). Pembrolizumab treatment demonstrated activity with response rate of 22% and disease control rate of 63% in PD-L1 unselected mesothelioma patients. Median PFS was 4.1 months (95% CI: 2.3- 6.2) and median OS was 11.5 months (95% CI: 7.6-14). Responses were observed in patients with any PD-L1 expression levels (none to ≥ 50%). Patients with high (≥ 50%) PD-L1 expression (n = 14) achieved higher response rate (43%, p = 0.021) and longer PFS (4.9 months, p = 0.034). Common grade 3/4 AEs included adrenal insufficiency (4.5%), pneumonitis (3%), and fatigue (3%). Grade 5 AEs were hepatitis and unknown (1.5% each). This study indicates that single-agent pembrolizumab is effective in PD-L1 unselected, previously-treated mesothelioma patients. Patients with high (≥ 50%) PD-L1 expression trended towards a higher response rate and longer PFS.

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