Immunotherapy Combinations "Raising the Bar"

August 2018 Vol 11, Special Issue - Immunotherapy
Phoebe Starr

Chicago, IL—Immunotherapy combinations are being studied intensively to determine which combinations hold the most promise in specific cancer types. At ASCO 2018, the session "Compelling Combinations: Raising the Bar with Immunotherapy," which featured 3 new studies that explore chemotherapy plus immunotherapy, got high marks from lead investigator Si­by­lle Loibl, MD, PhD, Co-chair of the German Breast Group, Neu-Isenburg, Germany, who discussed the results: durvalumab (Imfinzi) plus anthracycline/taxane chemotherapy in triple-negative breast cancer, pembrolizumab (Keytruda) plus chemotherapy in metastatic squamous non–small-cell lung cancer (NSCLC), and the poly (ADP ribose) polymerase (PARP) inhibitor niraparib (Zejula) plus immunotherapy with pembrolizumab for platinum-resistant ovarian cancer.
All 3 regimens will be studied further, and pembrolizumab plus chemotherapy appears to be a new standard of care for nonsquamous NSCLC.

Durvalumab in Triple-Negative Breast Cancer

The addition of durvalumab to anthra­cycline/taxane-based chemotherapy boosted the pathologic complete response (pCR) rate to 53% compared with 44% with chemotherapy alone as neoadjuvant therapy for early-stage triple-negative breast cancer in the randomized phase 2 GeparNuevo study. The responses were even better in a group of patients who received durvalumab alone during a 2-week window of opportunity to prime the immune system before receiving chemotherapy resulting in a pCR of 61% versus 41.4% with chemotherapy alone.

Speaking for the German Breast Group, Dr Loibl said, "Durvalumab should be investigated further in patients with primary triple-negative breast cancer. Induction therapy seems beneficial, especially in patients who start with durvalumab before chemotherapy, those with stage IIa and higher disease, and patients younger than age 40. The addition of durvalumab was well-tolerated."

Durvalumab is a checkpoint inhibitor FDA approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma and for stage III NSCLC; the drug is not yet approved in the triple-negative breast cancer setting.

The GeparNuevo study enrolled 174 patients with early-stage triple-negative breast cancer and stratified them according to tumor-infiltrating lymphocytes (TILs) level as low, medium, or high expression of TILs. The patients were randomized to durvalumab or to placebo for 2 weeks; then the experimental arm continued receiving nab-paclitaxel (Abraxane) plus durvalumab for 12 weeks, and the control arm received nab-paclitaxel alone. The patients were evaluated for clinical response, and the experimental arm received 4 cycles of chemotherapy (ie, epirubicin plus cyclophosphamide) plus durvalumab for 8 weeks, and the control arm received epirubicin plus cyclophosphamide alone for 8 weeks. Surgery was subsequently performed.

At baseline, the median age was 49.5 years; approximately 66% of patients had stage IIa or higher disease; and 38% had a low TIL level, 48% had a medium TIL level, and 14% had a high TIL level.

For the primary end point, the pCR rates were 53.4% in the durvalumab arm versus 44.2% in the chemotherapy-­alone (ie, the control) group, which was not statistically significant. In an analysis of predefined subgroups, the 117 patients who received "window" durvalumab did significantly better than the 57 patients who did not receive window durvalumab (P = .048; pCR of 61% vs 41.4%, respectively). For patients with stage IIa or higher disease, the pCR rates were 55.8% versus 38.6%, respectively, and for those aged <40 years, the pCR rates were 69.2% versus 42.9%, respectively.

The rates of grade 3/4 adverse hematologic events were 2.2% in the durvalu­mab arm and 2.4% in controls for anemia; 37.1% and 41.5%, respectively, for neutropenia; and 1.1% and 2.4%, respectively, for thrombocytopenia. Febrile neutropenia was reported in 4.3% and 2.4% of the patients, respectively.

"This trial suggests that a short lead-in with immunotherapy may be the best way to go with this combination. Monotherapy with checkpoint inhibitor prior to combination immunotherapy plus chemotherapy should be explored," stated the formal discussant of these 3 trials, Charles G. Drake, MD, PhD, Co-director, Immunotherapy Program, Herbert Irving Comprehensive Cancer Center at Columbia University, New York City.

KEYNOTE 407: Pembrolizumab plus Chemotherapy in NSCLC

The randomized, phase 3 KEYNOTE 407 clinical trial compared carboplatin (Paraplatin) plus paclitaxel (Taxol) or nab-paclitaxel plus pembrolizumab versus the same chemotherapy in patients with metastatic squamous NSCLC.

The study enrolled 559 patients with untreated stage IV disease and no symptomatic brain metastases. The patients were randomized to pembro­liz­umab plus chemotherapy followed by pembrolizumab maintenance therapy versus the same chemotherapy and no maintenance therapy.

At the ASCO meeting, Luis G. Paz-Ares, MD, PhD, Hospital Universitario 12 de Octubre, Madrid, Spain, presented the results of the second interim analysis with data cutoff as of April 2018.

At the time of the ASCO meeting, 121 patients were still ongoing in the pembrolizumab arm and 72 were continuing with chemotherapy. Overall, 42.8% of patients crossed over from the chemotherapy arm to the experimental arm.

The patients' median age was 65 years, and approximately 80% were males. Approximately 60% of the patients received paclitaxel rather than nab-paclitaxel.

Overall survival (OS) was significantly better in the pembrolizumab arm: 30.6% of patients had events versus 42.7% in the chemotherapy arm (P = .0008). The median OS was 15.9 months versus 11.3 months, respectively. A subgroup OS analysis showed a similar survival magnitude of benefit across all PD-L1–expression subgroups.

Progression-free survival (PFS) was also significantly improved with the addition of pembrolizumab to chemotherapy, with a median PFS of 6.4 months versus 4.8 months in the chemotherapy-alone arm (P <.0001). PFS was improved across all PD-L1 subsets, but the magnitude of improvement was greater in the patients who had greater PD-L1 expression.

The rates of response and duration of response were higher in the pembrolizumab arm.

The rate of adverse events was similar in both treatment arms. More immunotherapy-related events and more treatment discontinuations were reported in the pembrolizumab-containing arm.

"These data suggest that pembroliz­umab plus carboplatin and paclitaxel or nab-paclitaxel should become a new standard of care for squamous NSCLC," Dr Paz-Ares said.

"This study is clearly a win for squamous NSCLC, with median OS of 15.9 months versus 11.3 months. It is a beautifully positive trial, and this regimen will become a standard of care," stated formal discussant Dr Drake.

Platinum-Resistant Ovarian Cancer

"Platinum-resistant ovarian cancer represents an unmet need," stated Panagiotis A. Konstantinopoulos, MD, PhD, Director of Translational Research, Gynecologic Oncology Program, Dana-Farber Cancer Institute, Boston, who reported the results of the phase 1/2 TOPACIO trial evaluating the PARP inhibitor niraparib plus pembrolizumab in this setting.

The recommended doses for the phase 2 trial were niraparib 200 mg and pembrolizumab 200 mg.

The trial enrolled 60 patients with platinum-resistant and platinum-refractory ovarian cancer. More than 75% of the patients had BRCA wild-type ovarian cancer, and 57% had PD-L1–positive disease. Almost 66% had previously received bevacizumab.

The objective response rate was 25% in this heavily pretreated pop­ulation of patients with platinum-
resistant ovarian cancer.

"Clinical activity was observed across multiple subtypes, including BRCA wild-type, and PD-1–positive and –negative patients," Dr Konstantinopoulos said. "Responses were not limited to homologous repair deficient [HRD]-positive patients. Adding pembrolizumab to niraparib in BRCA wild-type and HRD-negative patients led to similar objective response rates as with PARP inhibition in BRCA-­mutated patients."

The median duration of response was 9.3 months. "This compares well with duration of response with olaparib in BRCA-mutated platinum-resistant patients," he said.

There were no new safety signals related to either drug.

"These results of a single-arm trial are stunning. The BRCA-ness and HRD status don't seem to matter with the combination of PARP inhibitor and checkpoint inhibitor. This is intriguing and needs to be studied further," Dr Drake stated. "We need a randomized trial."

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