Practice-Changing Findings

Mary Jo Fidler, MD

Inside ASCO 2015: Lung Cancer

Recent progress in lung cancer was a bright spot at the 2015 ASCO Annual Meeting. Several studies were presented that either are practice-changing or will likely lead to practice changes in the future.

Immune checkpoint inhibitors cause a stir

Results with immune checkpoint inhibitors were certainly the most anticipated and talked about during this Annual Meeting. The results of second-line trials of PD-1 and PD-L1 inhibitors vs docetaxel in patients with nonsquamous and squamous non–small-cell lung cancer (NSCLC) were particularly exciting. In the nonsquamous patients, nivolumab easily met its overall survival (OS) endpoint, with an OS of 12.2 months in the nivolumab arm compared with 9.4 months in the docetaxel arm.[1] Similar results were seen with nivolumab compared with docetaxel in the squamous NSCLC population (P = .00025), with a reduction in the risk of death of 41%, which was independent of PD-L1 positivity.[2]

The benefit of nivolumab in nonsquamous patients, however, seemed less pronounced in never-smokers and seems to be more associated with PD-L1 expression.[1] Other studies, involving atezolizumab and pembrolizumab (an anti–PD-L1 agent and an anti–PD-1 agent, respectively), also show that in trials including nonsquamous NSCLC patients, PD-L1 expression on tumor cells and tumor-infiltrating lymphocytes (TILs) is predictive of benefit from these agents.[3,4] Adenocarcinoma lung cancers with driver mutations are associated with never-smoking and have less tumor mutational burden. A group of investigators studied epidermal growth factor receptor EGFR mutation–positive and ALK-rearranged lung cancers for tumor PD-L1 expression and CD8-positive TILs before and after exposure to a targeted agent. In the cases studied, few tumors had high PD-L1 expression or a high number of TILs, and the expression did not change notably after exposure to EGFR or ALK tyrosine kinase inhibitors (TKIs), suggesting that PD-1–directed immune checkpoint inhibitors may not have as robust activity in lung cancers with driver mutations as in tumors with high mutational burden. Indeed, preliminary results in small-cell lung cancer (associated with an extremely high mutational burden) showed favorable rates of response to immune checkpoint inhibition, although the number of treated patients was low and follow-up short.[5,6] The toxicity profile of agents that target the PD-1 pathway is generally much more favorable than that of cytotoxic chemotherapy, making possible strategies such as adding a CTLA-4 blocker to PD-1 blockade, which has been proposed as a means of increasing the number of infiltrating cytotoxic T cells. Combination strategies with these two classes of agents are in early phases of testing.[6,7]

Good news for some patients with brain metastases

Practice-changing data were also presented on the treatment of patients with brain metastases. Mulvenna et al presented the results of a randomized controlled trial of whole-brain radiation plus dexamethasone vs supportive care plus dexamethasone in advanced NSCLC patients ineligible for whole brain–sparing procedures.[8] The trial showed a similar OS in both groups and no quality-of-life benefit for whole-brain radiation. However, 95% of the patients who were included had a class II or III Radiation Therapy Oncology Group recursive partitioning analysis (RPA), with expected median survival of 4.2 months or less, suggesting that this strategy may not be applicable to younger patients whose disease has been controlled with systemic therapy and who have good performance status. A second trial examining the benefit of local control provided by whole-brain radiation therapy following local treatment (with stereotactic radiosurgery [SRS]) of 1 to 3 brain metastases was presented; of the patients studied, the majority had lung cancer.[9] The study was powered at the 85% level to detect a 25% decrease in risk of cognitive progression if whole-brain radiation was omitted. Although the addition of whole-brain radiation to SRS was associated with less treatment failure in the brain, it was at the expense of decreased quality of life and had no OS benefit. Hopefully the results of this trial will reduce the number of patients with small-volume intracranial tumor burden who receive whole-brain radiation.

TKIs show promise-unto the third generation

Another area of excitement in lung cancer at ASCO 2015 was the progress that has been made in the use of EGFR TKIs. Multiple studies were presented suggesting promising activity for third-generation agents-and most of these were associated with relatively little toxicity. Some data were from the first-line setting, comparing the new agents to first-generation TKIs, but other studies focused on patients previously treated with EGFR TKIs. These trials focused in particular on efficacy in patients with the T790 mutation, the most common mechanism of resistance to first-line therapy. Rociletinib, in a reported phase I/II trial, had activity in both T790 mutation–positive and –negative patients, with response rates of 53% and 37%, respectively.[10] These results are possibly attributable to cross-reactivity of rociletinib with the insulin-like growth factor receptor 1 TKI. The initial grade 3/4 hyperglycemia rate of 22% in the lower-dose cohort was reduced to 8% with hyperglycemia monitoring and use of a treatment algorithm. These data were particularly exciting because they showed the feasibility of detecting T790 mutations in circulating tumor cells. There was an 81% agreement between plasma detection of T790 mutations and detection in tissue; moreover, the serum test was able to identify mutations in patients with inadequate tissue. Activity was promising for all agents for which data were presented; however, because of the immaturity of follow-up data, it remains to be seen whether there is benefit from starting treatment with third-generation agents.

Finally, notable studies investigating other molecular targets in lung cancer were presented. There were follow-up data demonstrating encouraging activity in BRAF-mutated and RET-rearranged tumors, as well as more promsing data with third-generation ALK TKIs. Phase II data were presented for alectinib, a third-generation ALK TKI, in patients who had progressed after crizotinib therapy.[11] In addition to an encouraging response rate of 50% and a median duration of response of 11.2 months, there was a documented 57% response rate in patients with measurable central nervous system (CNS) disease. This last result is particularly notable, since about 50% of crizotinib-treated patients have CNS progression.[12-14]

In sum, the 2015 ASCO Annual Meeting was an exciting one for oncologists who treat lung cancer. We saw the potential for meaningful progress in small-cell lung cancer, as well as advances in the use of immune checkpoint inhibitors in NSCLC and further advances in targeted therapy. Finally, data presented at this year’s meeting will allow us to skip whole-brain radiation therapy in select NSCLC patients with low tumor burden amenable to SRS and poor performance status/poor control of systemic disease who may not benefit from such treatment.

Financial Disclosure:Dr. Fidler has consulted for Bristol-Myers Squibb and Clovis, and has received a speaker honorarium from Genentech.

References:

1. Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr LBA109.

2. Spigel DR, Reckamp KL, Rizvi NA, et al. A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 8009.

3. Spira AI, Park K, Mazières J, et al. Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 8010.

4. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018-28.

5. Ott PA, Fernandez ME, Hiret S, et al. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 7502.

6. Antonia SJ, Bendell JC, Taylor MH, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 7503.

7. Patnaik A, Socinski MA, Gubens MA, et al. Phase 1 study of pembrolizumab (pembro; MK-3475) plus ipilimumab (IPI) as second-line therapy for advanced non-small cell lung cancer (NSCLC): KEYNOTE-021 cohort D. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 8011.

8. Mulvenna PM, Nankivell MG, Barton R, et al. Whole brain radiotherapy for brain metastases from non-small lung cancer: Quality of life (QoL) and overall survival (OS) results from the UK Medical Research Council QUARTZ randomised clinical trial (ISRCTN 3826061). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 8005.

9. Brown PD, Asher AL, Ballman KV, et al. NCCTG N0574 (Alliance): a phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr LBA4.

10. Sequist LV, Goldman JW, Wakelee HA, et al. Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 8001.

11. Ou SH, Ahn JS, De Petris L, et al. Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: an open-label, single-arm, global phase 2 study (NP28673). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 8008.

12. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33:1881-8.

13. Ou SH, Jänne PA, Bartlett CH, et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol. 2014;25:415-22.

14. Khozin S, Blumenthal GM, Zhang L, et al. FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. Clin Cancer Res. 2015;21:2436-9.