Dr Herbst began by describing that cancer cells, particularly lung cancer, have a high mutational burden that can make them appear as non-self to the immune system. The immune system can recognize and attack cancer cells, but one mechanism to evade the immune attack is for the tumor cell to express the PD-L1 molecule, which interacts with PD-1 on the cytotoxic T-cell. This PD-1/PD-L1 interaction leads to a downregulation of the immune response, and current immunotherapeutic approaches consist of antibodies that target either PD-1 or PD-L1 to prevent this interaction.
Several antibodies to PD-1 or PD-L1 are in development. These agents, also referred to as immune checkpoint inhibitors, include anti-PD-1 antibodies (nivolumab, pembrolizumab) and anti-PD-L1 antibodies (MPDL3280A, MEDI4736, MDX-1105). Another class of immune checkpoint inhibitors, including ipilimumab, targets the CTLA-4 molecule, although the development of anti-PD-(L)1 antibodies is the focus of this recap.
Dr Herbst explained that immune checkpoint inhibitors have generated much interest due to their activity in heavily pretreated patients, yielding single-agent overall response rates (ORRs) of approximately 15%-25%. Furthermore, subgroup analyses indicate activity of these agents in patients with squamous histology, and possibly also current/former smokers, 2 patient groups that have generally not been able to benefit from recently developed therapies. Most clinical data with the PD-(L)1 antibodies in lung cancer have been from phase II trials, but in January 2015, it was announced that the randomized phase III CheckMate-017 trial demonstrated improved overall survival with nivolumab compared with standard chemotherapy in previously treated patients with non-small-cell lung cancer and squamous histology; additional details are forthcoming.
While the adverse-event (AE) profile of anti-PD-(L)1 antibodies has generally been mild, the alterations of the immune system by these agents can lead to several organ systems being affected. These toxicities usually manifest as inflammatory reactions, including colitis, nephritis, pneumonitis, and dermatitis. On average, these AEs manifest themselves approximately 6-12 weeks after the start of therapy.
The challenge also remains to identify a predictive biomarker for these agents. While PD-L1 expression levels have been investigated, variation in assays and the presence of responders in apparently marker-negative patients has revealed the complexity of this therapeutic area. Efforts are ongoing to investigate other potential biomarkers, such as T-cell infiltration and gene expression signatures of T-cells.
The 9th Annual New York Lung Cancer Symposium®, which was held November 8, 2014, featured key lung cancer experts from the New York City area addressing best practices for the management of patients with lung cancer, as well as emerging therapeutic paradigms. This second of 3 PER Pulse™ Recaps from the Annual New York Lung Cancer Symposium® focuses on targeted agents for patients with non-small-cell lung cancer (NSCLC) and molecular aberrations in the epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genes.
Dr Halmos and Dr Pérez-Soler discussed optimal treatment for patients with EGFR mutations. In particular, for previously untreated patients, there are 3 EGFR tyrosine kinase inhibitors (TKIs) that are suitable, namely gefitinib (where available), erlotinib, and afatinib; there currently are no direct comparisons between the TKIs in this setting. Randomized phase II data suggest that the addition of bevacizumab to erlotinib could improve progression-free survival over erlotinib alone. Differences in outcome based on mutations in exon 19 versus exon 21 have been reported; Dr Pérez-Soler stated that although direct comparisons between the EGFR TKIs have not been done in patients with exon 19 deletions, it is reasonable to consider afatinib, as this agent has reported an overall survival (OS) benefit when compared with standard chemotherapy.
Several potential courses of action can be considered upon progression on EGFR TKIs, as described by Dr Lynch and Dr Riely. Due to different mechanisms of resistance, a rebiopsy is key to determining the best treatment. For patients with the T790M mutation, which accounts for resistance in approximately 50% of patients, several next-generation EGFR TKIs, such as rociletinib and AZD9291, have demonstrated response rates of approximately 70%. Other options, such as the combination of afatinib and cetuximab, have demonstrated activity in the context of T790M-negative resistance to an EGFR TKI. Dr Riely discussed the use of local therapy while continuing the TKI; this approach can be considered in patients with limited sites of progression, such as ≤4 sites outside of the central nervous system.
In patients with resectable lung cancer and EGFR mutations, Dr Chaft and Dr Halmos discussed the use of EGFR TKIs in the adjuvant setting. Compared with the metastatic setting, fewer data exist in the early-stage and locally advanced settings, but initial studies indicate that EGFR TKIs as adjuvant therapy can delay disease recurrence compared with observation. To follow up on these findings, randomized trials are investigating EGFR and ALK TKIs in patients with EGFR mutations or EML4-ALK rearrangements, respectively. These trials will be powered to detect a difference in OS, although the data will not mature for at least 10 years.
Dr Riely described the landscape for patients with EML4-ALK-rearranged NSCLC. The ALK TKI crizotinib is the current first-line standard of care, although a phase III trial is currently ongoing to compare a next-generation ALK TKI, alectinib, to crizotinib in this patient population. For patients who progress on crizotinib, Dr Riely explained that ceritinib has been approved; as with patients with EGFR mutations, patients with EML4-ALK-rearranged NSCLC and limited sites of progression may benefit from local therapy and continuation of the original ALK TKI.
The 9th Annual New York Lung Cancer Symposium®, which was held November 8, 2014, featured key lung cancer experts from the New York City area addressing best practices for the management of patients with lung cancer, as well as emerging therapeutic paradigms. This third of 3 PER Pulse™ Recaps from the New York Lung Cancer Symposium® focuses on recent data and future approaches for patients with non-small-cell lung cancer (NSCLC) and squamous cell histology, as presented by Dr Peter Hammerman and Dr Benjamin Levy.
Antiangiogenic agents have recently become a therapeutic option for patients with squamous NSCLC. Previous agents targeting the vascular endothelial growth factor (VEGF) ligand were associated with severe bleeding events, and patients with squamous histology were excluded from the pivotal trials. However, Dr Levy described that antibodies to the VEGF receptor 2 (VEGFR-2) have been studied in patients with both squamous and nonsquamous NSCLC in the phase III REVEL trial. Patients with 1 prior line of therapy received docetaxel with either placebo or the anti-VEGFR-2 antibody ramucirumab. The primary endpoint of overall survival was longer in the ramucirumab arm compared with placebo (10.5 months vs 9.1 months; P = .0235). Median progression-free survival and overall response rate also were increased in the ramucirumab arm. The overall incidence of grade ≥3 adverse events (AEs) was similar between the treatment arms; treatment-related AEs resulting in death occurred in 5% of patients in the ramucirumab arm and in 6% of patients in the placebo arm. The US Food and Drug Administration approved ramucirumab plus docetaxel for patients with previously treated NSCLC in December 2014.
Dr Hammerman described some of the molecular targets for patients with squamous NSCLC. Not surprisingly, these differ from the molecular targets that have been successfully targeted in patients with adenocarcinoma, including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Dr Hammerman mentioned that in patients with squamous NSCLC, molecular aberrations occur often in tumor suppressor genes and fibroblast growth factor receptor (FGFR) genes, with the latter experiencing amplification, mutation, and gene fusions. He commented that trials are accruing patients with squamous NSCLC, and encouraged participants to refer their patients, whenever possible, to undergo comprehensive genotyping.
For additional commentary about these topics and others, visit www.gotoper.com to access downloadable slides from the 9th Annual New York Lung Cancer Symposium®.
Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
This activity is not approved for AMA PRA Category 1 Credit™.
Supported by educational grants from AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Celgene Corporation, Clovis Oncology, Genentech, Lilly, Merck, Inc., and Novartis Oncology.
For further information concerning Lilly grant funding visit www.lillygrantoffice.com.
Dec 31, 2018
Medical Crossfire®: Defining New Roles for the Application of PARP Inhibition Strategies in Multiple Tumor Types
Dec 31, 2018
Dec 31, 2018