Search for Curative Therapies Continues in Lung Cancer

Paul A. Bunn Jr, MD

Curative strategies for patients with advanced lung cancer remain elusive despite several exciting advancements, according to Paul A. Bunn Jr, MD, and Primo N. Lara Jr, MD, who delivered keynote lectures during the 15th Annual International Lung Cancer Congress.

Progress in NSCLC

Survival has been substantially prolonged by new treatment strategies for patients with advanced non—small cell lung cancer (NSCLC). However, these advances have not yet culminated in a cure for patients, said Bunn, a professor of Lung Cancer Research at the University of Colorado School of Medicine in Denver and a winner of a 2014 Giants of Cancer Care award. Similarly, despite progress in small cell lung cancer (SCLC), extensive disease remains incurable, suggested Lara, the associate director of Translational Research at the UC Davis Comprehensive Cancer Center.In his talk, Bunn highlighted three primary approaches that have been utilized in the search for cure in NSCLC: large trials in unselected patients, molecular-based studies, and studies exploring immunotherapy with checkpoint inhibitors.

For the first point, Bunn drew on evidence from the phase III SQUIRE trial that explored the addition of necitumumab to gemcitabine and cisplatin compared with the chemotherapy alone among 1093 patients with squamous cell NSCLC.¹ In this study, the addition of necitumumab significantly improved overall survival (OS) and progression-free survival (PFS).

The median OS with necitumumab was 11.5 versus 9.9 months with chemotherapy alone (HR = 0.84; P = .012). The median PFS was 5.7 versus 5.5 months (HR = 0.85; P = .02) and the overall response rate (ORR) was 31% versus 29% (P = .40), for necitumumab and gemcitabine-cisplatin, respectively.

In a similar scenario, the phase III REVEL study randomized 1253 patients with NSCLC to receive either second-line ramucirumab added to standard docetaxel or docetaxel alone.² The addition of the VEGFR2 inhibitor improved OS by 1.4 months versus docetaxel alone (HR = 0.857; P = .0235). The median OS was 10.5 months in the ramucirumab arm versus 9.1 months in the docetaxel-alone arm. The survival benefit was upheld across most patient subgroups, including both squamous and nonsquamous histology.

"It’s easy to see that after many, many randomized trials in unselected patients that were either negative or with a tiny advantage that we're not going to cure patients by doing that type of trial," Bunn said. "That doesn't mean those trials shouldn't be done, but you're not going to cure anybody."

In selected populations, several clinical trials exploring tyrosine kinase inhibitors (TKIs) in NSCLC have demonstrated extensions in OS. However, resistance is common with these therapies, warranting the need for next-generation resistance-targeted agents.

For the 21% of patients with EGFR mutations, third-generation inhibitors have shown promise in early studies. The selective inhibitors of the EGFR T790M acquired resistance mutation, AZD9291 and CO-1686 have demonstrated impressive early results. Based on this early promise, both therapies have received the FDA's breakthrough therapy designation.

“Resistance is universal, and cells largely escape from the original TKI by a secondary gatekeeper mutations that changes the TKI binding pocket or by activating another signaling pathway,” Bunn said. “It is certainly interesting that third-generation EGFR TKIs that don’t bind to wild-type but do bind to the T790M gatekeeper mutations have shown very high response rates and very long durations of response.”

In a large phase I study, AZD9291 demonstrated an ORR of 64% without inducing dose-limiting toxicities in patients with T790M-mutant NSCLC.³ The median duration of response had not been reached at the time of the analysis, with the longest duration of response being >8 months.

In phase I and II studies looking at CO-1686, the ORR was 58% across all dose levels in trial participants with biopsy-confirmed T790M mutations.⁴ Additionally, both compounds did not induce the skin rash and diarrhea commonly associated with earlier generations of EGFR inhibitors.

For the 8% of patients with ALK mutations, crizotinib is an established frontline standard of care. Adding to this, the ALK inhibitor ceritinib (Zykadia) gained FDA approval for patients with NSCLC who progressed on crizotinib in April 2014. In the phase I ASCEND-1 trial, the ORR was 54.6% with ceritinib in patients who received prior crizotinib (n = 163).⁵ Additionally, the median duration of response to ceritinib was 7.4 months and the median PFS was 6.9 months (95% CI, 5.4-8.4) among previously treated responders.

Despite the ability to delay progression and prolong survival, targeted therapies have not produced a cure. "Molecular therapies improve quality and quantity of life but are unlikely to improve cure rates when used alone in any stage," Bunn said.

A variety of agents that target immune checkpoints have generated excitement as potentially curative therapies. The leading agents in this space target PD-1 or its ligand PD-L1. At this point it remains unclear whether one approach is superior to the other; however, direct PD-L1 inhibition allows PD-1 to still bind to PD-L2, which is thought to enhance efficacy and safety. Given the mechanism of action for these agents, PD-L1 expression may be indicative of response.

"Like everything else, selection with a biomarker in the long run is going to be the answer—not giving these agents to everybody who walks in the door—but time will tell," Bunn said. "Whether combinations of checkpoint inhibitors will be better than a single one has yet to be determined."

In a phase I study looking at 129 heavily pretreated patients, survival rates at one year with the PD-1 inhibitor nivolumab were 42% and 24% at two years.⁶ The median OS was 9.9 months (95% CI, 7.8-12.4).

Accrual has completed for two phase III studies examining nivolumab in heavily pretreated patients with stage IIIB/IV NSCLC. In the first study, 264 patients with squamous histology were randomized to docetaxel or nivolumab, with a primary endpoint of ORR and OS. In the second study, 574 patients with nonsquamous histology were randomized to docetaxel or nivolumab, with a primary endpoint of OS.

SCLC Research Progressing

"I would say, to know whether these agents have the ability to cure anyone, let's keep waiting. Let's not assume they do and certainly we can hope that they would," Bunn noted.The proportion of new patients diagnosed with lung cancer whose tumors are classified as SCLC has been in decline, as mostly all cases are associated with smoking. Traditionally, patients with stage I-III SCLC have been treated with curative intent using concurrent chemoradiotherapy.

Advances for patients with extensive stage IV SCLC remain elusive, with prophylactic cranial irradiation (PCI) representing the most exciting recent advance. However, in a phase III study presented at the 2014 ASCO Annual Meeting, PCI was found to have a detrimental effect on OS for patients with extensive SCLC.⁷ Although the average time to brain metastases was improved, the median OS was 10.1 with PCI versus 15.1 months without PCI (HR = 1.38; 95% CI, 0.95-2.01; P = .091).

"The question is how do we cure those with extensive disease," said Lara. "The most important breakthrough in the past decade had been PCI, until ASCO this year."

Radiation therapy remains a curative therapy for patients with limited disease; however, its role for patients with extensive SCLC continues to be explored. In the CREST trial, 495 patients responding to chemotherapy were randomized to thoracic radiotherapy (TRT) or no treatment. All patients in the study received PCI.⁸

PFS was improved by TRT (HR = 0.73; P = .001). The Kaplan-Meier curves for OS were consistent in both arms for the first 9 months; however, at 1 year, OS favored TRT but this was not statistically significant (HR = 0.84; P = .066). Interestingly, with longer follow-up, the survival curves showed distinct separation. At the 2-year assessment, 13% of patients remained alive in the TRT arm compared with 3% in the control arm (P = .004).

"This trial suggests that overall survival is better for those receiving thoracic radiation in extensive stage," Lara said. "I think the lesson to be learned here is that there are still some persistent lethal subclones that remain sensitive to DNA- damaging therapies. These data reiterate our enthusiasm to test DNA-damaging therapies for this disease, such as PARP inhibitors and novel cytotoxics."

At this point, the best option for patients with extensive SCLC who progress on frontline therapy is a clinical trial, Lara explained. Few effective options are available in this setting, resulting in a median OS of only 2-3 months. Adding to this, recent data suggest that platinum sensitivity is not associated with OS.

"Even the platinum-sensitive status that we held dear for 20 years has diminished relevance," Lara said.

Combination chemotherapy has demonstrated promise in the second-line setting for patients who remain chemotherapy sensitive. A randomized phase III study demonstrated that treatment with a triplet of cisplatin, etoposide, and irinotecan improved OS by 33% compared with single-agent topotecan for patients with relapsed SCLC (HR = 0.67; P = .0079).⁹ The median OS was 18.2 versus 12.5 months and the median PFS was 5.7 versus 3.6 months for the triplet and topotecan, respectively.

However, the triplet was associated with significantly more grade 3/4 side effects, specifically anemia (84.4% vs 27.8%), thrombocytopenia (41.1% vs 27.8%), diarrhea (7.8% vs 0%), and febrile neutropenia (31.1% vs 6.7%).

In addition to the continued exploration of radiotherapy and chemotherapy, clinical trials continue to assess targeted treatments for patients with SCLC. Unfortunately, many already established approaches have faltered in clinical trials. For future efforts, studies have identified key somatic driver mutations that could be targeted.

"We now have a blueprint for the biology of small cell carcinoma," Lara explained. "I think the way to cure small cell is to find the stem of small cell biology. We need to find a way to target TP53 and RB1, which are tumor suppressors. If we can wake them up, we might get closer to the cure."

Immunotherapy with checkpoint inhibitors could also be explored for patients with SCLC. In a phase III study, the CTLA-4 checkpoint inhibitor ipilimumab is being combined with etoposide and platinum-based chemotherapy for patients with newly diagnosed advanced SCLC.¹⁰ The study hopes to enroll 1125 patients, with early results expected in November 2015.

"Cure is elusive in small cell lung cancer, whether it is limited or extensive stage,” Lara said. “New potential therapeutic targets have been identified, but unfortunately the likelihood of success is unknown. The checkpoint inhibitors need to be formally studied in small cell, because I believe that is where we need to be going."

References:

1. Thatcher N, Hirsch FR, Szczesna A, et al. A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non—small cell lung cancer (sq-NSCLC). J Clin Oncol. 2014;32:5s (suppl; abstr 8008).
2. Pérol M, Ciuleanu T-E, Arrieta O, et al. REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy. J Clin Oncol. 2014;32:5s (suppl;abstr LBA8006).
3. Jänne PA, Ramalingam, SS, Yang JC-H, et al. Clinical activity of the mutant- selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor— resistant non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32:5s(suppl; abstr 8009).
4. Sequist LV, Soria J-C, Gadgeel SM, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). J Clin Oncol. 2014;32:5s (suppl; abstr 8010).
5. Kim D-W, Mehra R, Tan DSW, et al. Ceritinib in advanced anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC): results of the ASCEND-1 trial. J Clin Oncol. 2014;32:5s (suppl; abstr 8003).
6. Brahmer JR, Horn L, Antonia SJ, et al. Nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial. Presented at: 15th World Conference on Lung Cancer; October 27-30, 2013; Sydney, Australia. Abstract MO18.03.
7. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): results of a Japanese randomized phase III trial. J Clin Oncol. 2014;32:5s (suppl; abstr 7503).
8. Goto K, Ohe Y, Seto T, et al. A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and irinotecan versus topotecan as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology Group study JCOG0605. J Clin Oncol. 2014;32:5s (suppl; abstr 7504).
9. Slotman BJ, Faivre-Finn C, van Tinteren H, et al. Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small cell lung cancer. J Clin Oncol. 2014;32:5s (suppl; abstr 7502).
10. NIH Registry. www.ClinicalTrials.gov. Identifier: NCT01450761.

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