The recently concluded meeting of the 15th International Association for the Study of Lung Cancer (IASLC) in Denver featured several presentations on various aspects related to the biology, treatment, and prevention of lung cancer (http://library.iaslc.org).
The proposed changes regarding the upcoming revised 8th edition of TNM staging system for lung cancer were presented, and a summary of those proposed changes are reviewed by Saiama N. Waqar, MBBS, MSCI in this issue of OT (see page 6).
Several papers presented at the conference provided updated results of immune checkpoint inhibitors and novel molecularly targeted drugs. I mention a few presentations here briefly:
Nivolumab
With longer follow-up, nivolumab continues to demonstrate improved survival compared with docetaxel in patients with metastatic non-small cell lung cancer (NSCLC). The median overall survival rate in the CheckMate 017 study was 9.2 months with nivolumab versus 6.0 months with docetaxel (HR -0.62, p=0.0004). The 18-month overall survival rate with nivolumab was 28 percent compared with only 13 percent with docetaxel.
Results from the CheckMate 012 study, the combination of nivolumab and ipilimumab, in previously untreated patients, showed encouraging overall response rates (13% to 39%) and median progression-free survival (ranging from 4.9 to 10.6 months).
A Phase III study (CheckMate 227; NCT 02477826) comparing nivolumab, nivolumab, and ipilimumab or platinum-based doublet chemotherapy is currently enrolling patients with chemotherapy-naive metastatic NSCLC.
Small Cell Lung Cancer
Despite considerable efforts, we have not made significant progress in the systemic therapy for patients with small cell lung cancer for a few decades. The results of a Phase I study of rovalpituzumab tesirine (Rova-T), an antibody drug conjugate targeting Delta-like Ligand (DLL)-3, are quite noteworthy: DLL-3 is normally expressed during development and is aberrantly expressed in small cell lung cancer tumor initiating cells. In this Phase I study of 80 patients, 73 (91%) had small cell lung cancer and seven (9%) had large-cell carcinoma with neuroendocrine features.
All patients had to have progressive disease following initial chemotherapy. Tumor samples were available from 63 percent of patients, and the majority of the samples examined (70%) had high DLL3 expression. The dose-limiting toxicities (DLT) were thrombocytopenia and serosal effusion at the 0.8 mg level.
The expansion cohort included 60 patients who received Rova T at the dose level of 0.2 mg q3 weekly and 0.3 mg q 6 weekly. The most common grade 3/4 side effects at the recommended Phase II dose, 0.3 mg q 6 weekly, were thrombocytopenia (15%), fatigue (5%), rash (5%), and edema (3%). The overall response rate in the expansion cohort of 60 patients (regardless of DLL3 expression levels) at two different dose levels was 20 percent, with an additional 57 percent showing evidence of anti-tumor activity.
In the DLL3-positive group the overall response rate was 39 percent, with 75 percent showing evidence of clinical benefit (stable disease and minor responses). The mean duration of response at the dose of 0.3 mg q6 weeks was 182+ days (range of 50 to 332 days).
Anecdotally, significant areas of necrosis and a significant drop in Ki-67 (marker of proliferation) were observed in resected tissue samples following treatment with Rova-T. Further studies are being planned to evaluate Rova-T in patients with small cell lung cancer.
These results are certainly very encouraging considering the challenges we have had in developing effective therapies for patients with relapsed small cell lung cancer. Other ongoing studies including those evaluating PARP inhibitors and immune checkpoint inhibitors in relapsed small cell lung cancer hopefully will change the prospects for patients with recurrent/relapsed small cell lung cancer.
Metastatic NSCLC
The addition of cetuximab to chemotherapy has shown modest improvement in overall survival in patients with metastatic NSCLC. Similarly, bevacizumab in combination with paclitaxel and carboplatin was found to be superior to paclitaxel and carboplatin alone.
The Southwest Oncology Group (SWOG) investigators conducted a Phase II trial of carboplatin/paclitaxel with cetuximab/bevacizumab followed by cetuximab/bevacizumab in patients with metastatic NSCLC (SWOG 0536). Even though it was merely a feasibility study (primary endpoint: incidence of grade 4 hemorrhage), 54 percent of patients had a partial response and overall survival was 15 months.
Based on these data, a large Phase III study (SWOG 0819) was conducted to evaluate the efficacy of the four-drug regimen. In this study (presented at the IASLC conference), 1,333 patients were enrolled, with 656 randomized to receive cetuximab and 657 randomized to the control group (20 were deemed ineligible).
Within each group, nearly 40 percent of patients were considered to be appropriate to receiver bevacizumab. Unfortunately, the study did not meet the two primary endpoints (progression-free survival in the EGFR FISH+ population and overall survival in the entire study population). The median overall survival durations with and without the addition of cetuximab in the entire population were 10.9 and 9.4 months, respectively with an HR of 0.94 (0.84-1.06). The median progression-free survival times in the EGFR FISH+ (n=400) patients with and without the addition of cetuximab were 5.4 and 4.8 months, respectively, with an HR of 0. 91 (0.74-1.12).
Notwithstanding the analysis of a small subset of EGFR FISH + squamous cell NSCLC (n-111) where overall survival durations with and without cetuximab were 11.8 and 6.4 months, with an HR of 0.56 (0.37-0.84), these results are quite disappointing. The addition of cetuximab to paclitaxel, carboplatin, and bevacizumab does not improve overall survival or progression-free survival.
E1505
The meeting also included the much-anticipated results of the E1505 randomized Phase III trial of adjuvant chemotherapy with or without bevacizumab in patients with resected NSCLC.
From July 2007 to September 2013, 1,501 patients were enrolled in the study. When the independent Data Safety Monitoring Committee (DSMC) conducted its sixth planned interim analysis, a decision was made to discontinue the study due to futility. At that time of discontinuation, the median follow-up was 41 months.
Approximately 15 percent of patients were deemed ineligible (the most common reason was inadequate nodal sampling, 7%) and two percent of patients never started their assigned therapy. Overall, 749 patients were randomized to chemotherapy and 752 to chemotherapy and bevacizumab.
Patients were treated with one of the four cisplatin-containing chemotherapy regimens (with vinorelbine, docetaxel, gemcitabine, or pemetrexed). Approximately 28 percent of patients had squamous histology, and a similar number had stage IB (T2N0 by AJCC 6th edition) NSCLC.
Bevacizumab was associated with an increased incidence of hypertension and overall worse grade 3/4 toxicities; there were no increased deaths observed compared with the use of chemotherapy alone. Unfortunately there was no improvement in overall survival with the addition of bevacizumab to adjuvant chemotherapy (HR 0.99) or disease-free survival (HR 0.98).
Moving Forward
As we move forward, we will have to work hard to refine biomarkers to optimally select patients for immune checkpoint inhibitors and explore novel ways to substantially increase the modest gains we have made with the use of these agents.
Ongoing studies will define the utility of using immune checkpoints in the frontline setting. There is now a glimmer of hope for patients with relapsed SCLC given the results from the Phase I study of Rova-T mentioned above and from immune checkpoint inhibitors presented this spring at the American Society of Clinical Oncology Annual Meeting.
Molecularly targeted therapies for EGFR-mutated and ALK-rearranged NSCLC are being studied as a part of the large ALCHEMIST trial currently ongoing in the U.S. Adjuvant therapy studies using immune checkpoint inhibitors are being developed at this time.
The outlook for patients with lung cancer continues to improve and there are now many reasons to remain optimistic.