Immunotherapies, in particular checkpoint inhibitors targeting programmed cell death-1 (PD-1) or programmed death ligand 1 (PD-L1), have continued to improve outcomes for more cancer patients. With the latest evidence presented at the European Society for Medical Oncology (ESMO) 2018 Congress, the therapeutic potential of the PD-1/PD-L1 inhibitors was demonstrated in different types of cancers, including triple-negative breast cancer (TNBC) and head and neck squamous cell carcinoma (HNSCC).
IMpassion130: Atezolizumab plus nab-paclitaxel for metastatic TNBC
Triple-negative breast cancer (TNBC) is known to be a notoriously aggressive and difficult-to-treat subtype of breast cancer.1 Single-agent taxane or anthracycline chemotherapy is the mainstay of treatment for TNBC in the metastatic settings, but the results of treatment remain unsatisfactory.1,2 Amongst the different subtypes of breast cancers, however, TNBC is the subtype found to be immunogenic, and therefore a promising candidate for immunotherapy.1-3
“IMpassion130 is the first phase III trial to demonstrate a benefit with first-line immunotherapy in TNBC,” said Dr. Peter Schmid of the Barts Cancer Institute-Queen Mary University of London, UK.4 The trial, which randomized 902 women with untreated metastatic TNBC in a 1:1 ratio to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel (Figure 1), not only found a significant benefit in progression-free survival (PFS) in the atezolizumab arm, but also a ‘clinically meaningful benefit’ in both PFS and overall survival (OS) in PD-L1+ patients receiving atezolizumab plus nab-paclitaxel.2,3
PFS and OS were the co-primary endpoints in the trial, assessed in both the intention-to-treat (ITT) population and PD-L1+ subgroup, but formal testing of OS in the PD-L1+ subgroup would only be done if significant OS benefit was seen in the ITT population.2,3 With the median follow-up duration of 12.9 months in the ITT population, the analysis presented at ESMO 2018 represent the final analysis for PFS and initial interim analysis for OS.2,3
As compared to nab-paclitaxel alone, atezolizumab plus nab-paclitaxel produced a significantly longer PFS in both the ITT population (stratified HR=0.80; 95% CI: 0.69-0.92; p=0.0025) and PD-L1+ subgroup (stratified HR=0.62; 95% CI: 0.49-0.78; p<0.0001).2,3 Median PFS in the ITT population was 7.2 months in the atezolizumab arm and 5.5 months in the placebo arm.2,3 Median PFS in the PD-L1+ subgroup was 7.5 months in the atezolizumab arm and 5.0 months in the placebo arm.2,3
The subgroup analysis in the ITT population has also revealed that “the benefit in terms of PFS is consistent across all subgroups, with the exception of PD-L1 expression,” Dr. Schmid said. “Practically all of the benefits were seen in the subgroup of patients with PD-L1+ tumors, whereas there was no benefit in terms of PFS in patients with PD-L1+ tumors.”2
Interim OS analysis in the ITT population, meanwhile, did not find a significantly longer OS with atezolizumab plus nab-paclitaxel (stratified HR=0.84; 95% CI: 0.69-1.02; p=0.084).2,3 At data cut-off, the median OS was 21.3 months in atezolizumab arm and 17.6 months in the placebo arm.2,3 Although formal OS testing in the PD-L1+ subgroup was not performed as per the hierarchical study design, the OS was found to be considerably longer in PD-L1+ patients who received atezolizumab plus nab-paclitaxel (median 25 months vs. 15.5 months with nab-paclitaxel alone; stratified HR=0.62; 95% CI: 0.45-0.86).2,3
In terms of safety, the most common adverse events (AEs) were generally similar between the treatment arms.2,3 Neutropenia, decreased neutrophil count, fatigue, and anemia were the most common grade 3-4 AEs that occurred with similar rates between the treatment arms, but grade 3-4 peripheral neuropathy was more common in the atezolizumab arm (6% vs. 3% in the placebo arm).2,3
“IMpassion130 is the first positive phase III immunotherapy study in TNBC, an aggressive disease with limited treatment options,” said Dr. Sandra Horning, Chief Medical Officer and Head of Global Product Development at Genentech. “Highly encouraged by these results, we plan to submit to authorities globally with the aim of bringing this combination to people with TNBC as soon as possible.”5
KEYNOTE-048: Pembrolizumab with or without chemotherapy for recurrent or metastatic (R/M) HNSCC
A large body of evidence supports the notion that immune evasion plays an important role in the recurrence and metastasis of HNSCC, thus a plethora of novel immunotherapeutic strategies are being investigated in this area.6,7 Pembrolizumab and nivolumab, another PD-1 inhibitor, have already been approved as a second-line treatment for R/M HNSCC, and it is also believed that chemotherapy could be a rational combination partner for the PD-1/PD-L1 inhibitors to treat the disease.6,7 “[Chemotherapy] disrupts tumor architecture and may overcome immune exclusion, results in antigen shedding, and induces rapid disease control,” said Prof. Barbara Burtness of the Yale School of Medicine, US.
After randomizing 882 patients with HNSCC who had not received prior chemotherapy or biologic therapy for recurrent or metastatic disease in a 1:1:1 ratio to cetuximab plus standard platinum-based chemotherapy or pembrolizumab alone or the combination of pembrolizumab and platinum-based chemotherapy, two comparisons of the phase III KEYNOTE-048 study were presented at the meeting.8 First is the comparison between pembrolizumab arm versus chemotherapy arm, and the second is the comparison between combination arm versus chemotherapy arm.8 The co-primary endpoints in the trial were OS and PFS. The median follow-up in this interim analysis were 11.7 months, 13.0 months, and 10.7 months for pembrolizumab arm, combination arm, and chemotherapy arm, respectively.8
In the first comparison, which assessed the subgroup of patients with combined positive score (CPS) ≥20 or CPS ≥1, OS was significantly longer in the pembrolizumab arm than chemotherapy arm.8 Pembrolizumab alone produced a significantly longer median OS of 14.9 months in the CPS ≥20 subgroup (vs. 10.7 months in the chemotherapy arm; HR=0.61; 95% CI: 0.45-0.83; p=0.0007) and 12.3 months in the CPS ≥1 subgroup (vs. 10.3 months in the chemotherapy arm; HR=0.78; 95% CI; 0.64-0.96; p=0.0086).8
Improvements in PFS, however, were only numerically higher with pembrolizumab in both CPS subgroups.8 Objective response rate (ORR), a secondary endpoint, were lower with pembrolizumab (23.3% vs. 36.1% for CPS ≥20; 19.1% vs. 34.9% for CPS ≥1), but Prof. Burtness added that “in both subsets (CPS ≥20 and CPS ≥1), the patients who obtained a response to pembrolizumab enjoyed a substantially longer duration of response (DOR) at 20.9 months.”8
In the second comparison, which assessed the whole population in the trial, pembrolizumab plus platinum-based chemotherapy produced a significantly longer OS of 13 months (vs. 10.7 months in the chemotherapy arm; HR=0.77; 95% CI: 0.63-0.93; p=0.0034).8 Similar with the first comparison, significant benefit in PFS in the combination arm was not seen in the second comparison.8 ORR was similar between the combination arm (35.6%) and chemotherapy arm (36.3%), but DOR was longer with pembrolizumab plus chemotherapy (6.7 vs. 4.3 months).8
No unexpected safety concerns have been identified in the three treatment arms, with pembrolizumab alone being less toxic than cetuximab plus chemotherapy (grade 3-5 treatment-related AEs: 16.7% vs. 69.0%), and similar toxicities between the combination arm and chemotherapy arm (grade 3-5 treatment-related AEs: 71.0% vs. 69.0%).8 Across the board, the most common immune-mediated AE with the pembrolizumab arms was grade 1-2 hypothyroidism.8
“Pembrolizumab appears to prolong life even when the cancer continues to grow, suggesting that it should be a first line therapy in recurrent and metastatic head and neck cancer,” Prof. Burtness said. “Whether pembrolizumab is given alone or with chemotherapy may depend on PD-L1 expression and we are conducting analyses to answer this question.”9
Exciting developments with other PD-1/PD-L1 inhibitors
Other than atezolizumab in IMpassion130 and pembrolizumab in KEYNOTE-048, exciting developments from other PD-1/PD-L1 inhibitors were also reported at the meeting.
For microsatellite instability (MSI)-high metastatic colorectal cancer, nivolumab plus low-dose ipilimumab in the first-line setting produced 60% ORR and 84% disease control rate (DCR).10 Median DOR, PFS, and OS were not yet reached at a median follow-up of 13.8 months in the phase 2 CheckMate-142 trial.10
The phase III ARCTIC evaluated durvalumab monotherapy (for PD-L1 TC [tumor cells] ≥25%) and durvalumab plus tremelimumab (for PD-L1 TC <25%), as third-line and beyond therapy, in the heavily pretreated advanced non-small-cell lung carcinoma (NSCLC) patients.11 Comparisons were made against erlotinib, gemcitabine, or vinorelbine as the standard of care (SoC).11 In this study, durvalumab monotherapy produced a clinically meaningful OS improvement in PD-L1 TC ≥25% patients (HR=0.63; 95% CI: 0.42-0.93), but durvalumab plus tremelimumab only produced a non-significant numerical OS improvement in PD-L1 TC <25% patients.11
Avelumab plus axitinib in the JAVELIN Renal 101 trial, on the other hand, produced the first positive phase 3 data of immunotherapy and a tyrosine kinase inhibitor (TKI) combination in previously untreated patients with advanced renal cell carcinoma (RCC).12 As compared to those receiving sunitinib, the ORR and PFS were almost doubled regardless of PD-L1 expression.12 PFS as per blinded independent central review was 13.8 months vs. 7.2 months for the combination arm and sunitinib arm respectively (stratified HR=0.61; 95% CI: 0.47-0.79; 1-sided p<0.0001).12
The latest addition to the family of PD-1/PD-L1 inhibitors, cemiplimab, is also being investigated in a phase 2 study of patients with advanced basal cell carcinoma (BCC) who experienced disease progression or are intolerant to hedgehog inhibitors (HHI) therapy.13 With its recent U.S. Food & Drug Administration (FDA)’s approval as treatment of patients with metastatic cutaneous squamous
cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation, the potential of cemiplimab in other types of cancers remains to be seen.14
Following the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO) held earlier this year, the new evidence presented at the ESMO 2018 Congress continued to explore the therapeutic potential of immunotherapy, either alone or in synergy with different classes of medications. There remain unanswered questions, but there is no doubt that the remarkable advances of immunotherapy in different types of cancers are a promising sign of what’s to come.
1. Jia H, Truica CI, Wang B, et al. Immunotherapy for triple-negative breast cancer: Existing challenges and exciting prospects. Drug Resist Updat. 2017;32:1-15.
2. Schmid P, Adams S, Rugo HS, et al. IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). 2018 ESMO Congress; Munich, Germany; October 19-23, 2018. Abstract LBA1_PR.
3. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018 [Epub ahead of print].
4. Some patients with metastatic triple negative breast cancer live longer with immunotherapy. ESMO 2018 Press Release. 2018 (Accessed October 22, 2018, at https://www.esmo.org/Press-Office/Press-Releases/IMpassion130-atezolizumab-nab-pac-triple-negative-breast-cancer-Schmid?hit=ehp).
5. IMpassion130: Atezolizumab Plus Nab-Paclitaxel in Metastatic or Locally Advanced Triple-Negative Breast Cancer. The ASCO Post. 2018 (Accessed October 22, 2018, at http://www.ascopost.com/News/59027).
6. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-1867.
7. Economopoulou P, Agelaki S, Perisanidis C, et al. The promise of immunotherapy in head and neck squamous cell carcinoma. Ann Oncol. 2016;27(9):1675-85.
8. Burtness B, Harrington KJ, Greil R, et al. KEYNOTE-048: Phase III study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). 2018 ESMO Congress; Munich, Germany; October 19-23, 2018. Abstract LBA8_PR.
9. Immunotherapy improves survival in metastatic or recurrent head and neck cancer. ESMO 2018 Press Release (Accessed October 26, 2018, at https://www.esmo.org/Press-Office/Press-Releases/KEYNOTE048-head-neck-cancer-immunotherapy-Burtness).
10. Lenz HJJ, Cutsem EV, Limon ML, et al. Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). 2018 ESMO Congress; Munich, Germany; October 19-23, 2018. Abstract LBA18_PR.
11. Kowalski DM, Reinmuth N, Orlov SV, et al. ARCTIC: durvalumab + tremelimumab and durvalumab monotherapy vs SoC in _3L advanced NSCLC treatment. 2018 ESMO Congress; Munich, Germany; October 19-23, 2018. Abstract 13780.
12. Motzer RJ, Penkov K, Haanen JB, et al. JAVELIN Renal 101: A randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). 2018 ESMO Congress; Munich, Germany; October 19-23, 2018. Abstract LBA6_PR.
13. Lewis KD, Fury MG, Stankevich E, et al. Phase II study of cemiplimab, a human monoclonal anti-PD-1, in patients with advanced basal cell carcinoma (BCC) who experienced progression of disease on, or were intolerant of prior hedgehog pathway inhibitor (HHI) therapy. 2018 ESMO Congress; Munich, Germany; October 19-23, 2018. Abstract 1240TiP.
14. FDA approves cemiplimab-rwlc for metastatic or locally advanced cutaneous squamous cell carcinoma. FDA News Release. 2018 (Accessed October 29, 2018, at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm622251.htm).