Remarkable Six Months for Treatment Options in NSCLC

Checkpoint Inhibitors

Nivolumab

In March 2015, the US Food and Drug Administration (FDA) approved Bristol-Myers Squibb’s checkpoint inhibitor nivolumab for NSCLC. Its clinical trial results led the FDA to approve the treatment for patients with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy.¹Approval was based on data from a phase II trial (CheckMate-063 single arm)²and a phase III trial (CheckMate-017, nivolumab vs docetaxel). Patients treated with nivolumab experienced statistically significant overall survival (OS) versus patients treated with docetaxel. At ASCO 2015, results of the phase III CheckMate 057 trial showed statistically significant improvement in OS for nivolumab versus docetaxel in patients with nonsquamous NSCLC who failed previous platinum-based chemotherapy.³It is now approved in Europe for the treatment of patients with squamous NSCLC based on the results of the CheckMate 063 and 017 trials.

Pembrolizumab

On April 19, 2015, Merck filed for FDA approval of pembrolizumab for the treatment of patients with advanced NSCLC based on the results of its phase I 001 trial.⁴The trial recruited 495 patients. Programmed cell death ligand 1 (PD-L1) expression was assessed in tumor samples from a validation group. The objective response rate (ORR) was 19.4%, median duration of response (DOR) was 12.5 months, and median duration of progression-free survival (PFS) was 3.7 months for all patients. In patients with PD-L1 expression in at least 50% of tumor cells, the response rate was 45.2%, and the median PFS was 6.3 months.^5,6A decision from the FDA is expected on October 2, 2015.

Atezolizumab

Data were presented at ASCO 2015 on single-agent atezolizumab (Roche, previously known as MPDL3280A). The FIR study recruited patients with metastatic NSCLC who were previously treated with other therapies and who were chemotherapy naïve. The ORR was greater in patients who had tumors with high PD-L1 expression.⁷At the same meeting, the results of the POPLAR study showed that atezolizumab versus docetaxel improved OS, PFS, and ORR in previously treated patients with squamous or nonsquamous NSCLC. Once again, response was most evident in patients with high expression of PD-L1.⁸

Combination of MEDI4673 and tremelimumab

A phase Ib study shows that the combination of Astra Zeneca’s MEDI4673, a monoclonal antibody to PD-L1, and tremelimumab, an anti-cytotoxic T-lymphocyte—associated protein-4 (CTLA-4), is safe and demonstrates clinical activity in patients with advanced NSCLC. Activity was noted in PD-L1–negative and PD-L1–positive tumors, and the combination will move into phase III.⁹

Anti-EGFR, Anti-VEGF

Necitumumab

An FDA committee met on July 9, 2015, to consider data on necitumumab, an anti-EGFR antibody. In a press release, Lilly said it was encouraged by the discussions it had with the FDA regarding the risk-benefit profile of the drug. The combination of necitumumab with gemcitabine and cisplatin demonstrated a significant improvement in OS over chemotherapy alone, specifically in the first-line setting.^10,11

Bevacizumab

The results have been published of a randomized, open-label, phase II study of bevacizumab, an established anti-VEGF-A agent, with erlotinib versus erlotinib alone as first-line therapy in patients with advanced NSCLC withEGFRmutations.¹²The median PFS was 16 months (95% confidence interval [CI], 13.9-18.1) for the combination versus 9.7 months (95% CI, 5.7-11.1). OS data have not matured, and the authors state that a randomized phase III trial will be needed to confirm the efficacy of the combination.

Small Molecule Inhibitors

Motesanib

Early in 2015, Takeda announced the failure of its phase III study (MONET-A) testing motesanib (AMG 706) to meet its primary endpoint of PFS. Motesanib, an orally administered inhibitor of VEGF receptors, platelet-driven growth factor receptors, and stem cell growth factor, was administered to patients with advanced nonsquamous NSCLC in combination with carboplatin and paclitaxel.¹³

Rociletinib

Encouraging data for rociletinib, a third-generation inhibitor of EGFR, was published in theNew England Journal of Medicine.¹⁴Rociletinib (CO-1686) has activity against NSCLC that has developed resistance to EGFR therapy, usually mediated byT790Mresistance mutation. A phase I/II study demonstrated that patients who had failed prior EGFR treatment, and had theT790Mmutation, achieved an ORR of 59%. Ongoing trials include Tiger 1 (NCT02186301), a phase II versus erlotinib; Tiger 2 (NCT02147990), a phase II as second-line treatment in mutated NSCLC; and a phase III Tiger 3 (NCT02322281) versus chemotherapy in patients who have previously failed EGFR therapy. Clovis Oncology hopes to submit anewdrugapplicationsome time in 2015.¹⁵

AZD9291

AZD9291 (AstraZeneca) is another third-generation EGFR inhibitor with activity against theT790Mresistance mutation. Encouraging results of a phase I/II study demonstrated therapeutic benefit in patients with NSCLC who harbored theT790Mmutation and who had failed previous anti-EGFR therapy with a tyrosine kinase inhibitor. A response rate of 61% was reported in patients with the mutation.¹⁶

Afatinib versus erlotinib

In a phase III study, treatment with afatinib (Boehringer Ingelheim) resulted in significantly superior PFS and OS versus erlotinib in patients with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after ≥4 cycles of platinum-based chemotherapy.¹⁷The study authors concluded that afatinib could be an option for patients with squamous cell carcinoma of the lung. Afatinib was approved in 2013 for the first-line treatment of patients with metastatic NSCLC whose tumors haveEGFRexon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.¹⁸

Alectinib

A media release in May 2015 from Roche announced that the company had plans to submit its phase I/II data to the FDA as part of a new drug application for alectinib for the treatment ofALK-positive NSCLC. Alectinib, an ALK inhibitor that can cross the blood-brain barrier, has been granted breakthrough therapy designation.¹⁹The data were presented at ASCO 2015. In the phase II study, the ORR for patients with central nervous system metastases was high, at 68.8%.²⁰

Dabrafinib and trametinib combination

Data from a phase II trial supporting the combination of dabrafenib and trametinib in patients withBRAF V600E-mutated metastatic NSCLC were presented at ASCO 2015. The ORR was 68% by independent review, superior (by indirect comparison) to dabrafenib monotherapy. A financial statement released by Novartis stated that the combination has been granted breakthrough therapy status by the FDA.^21,22

Gefitinib

In July, the FDA approved gefitinib (AstraZeneca) for the first-line treatment of patients with metastatic EGFR-positive NSCLC expressing the most commonEGFRmutations (exon 19 deletions or exon 21L858Rsubstitution gene mutations). The FDA also approved the therascreen^®EGFR RGQ PCR Kit to permit identification of candidate patients for treatment with gefitinib.²³The approval was based on the results of the phase IV IFUM trial (NCT01203917).²⁴

Crizotinib

Pfizer announced it had received breakthrough therapy designation from the FDA for crizotinib. The designation was based on the results of a phase I study of patients withROS1-positive NSCLC. The trial recruited 50 patients with advanced ROS1+ NSCLC and achieved an ORR of 72% and median PFS of 19.2 months.^25,26

Veliparib

Poly ADP ribose polymerase (PARP) inhibitors are in development for NSCLC. At the ASCO 2015 meeting, data were presented from a phase II trial of veliparib (AbbVie) with carboplatin (C) and paclitaxel (P), versus placebo with C and P, showing that smoking was a strong predictor of veliparib efficacy. These results are important because outcomes for tobacco-related NSCLC are poor. A phase III trial has been initiated in patients with a history of smoking.²⁷

Novel Developments

With immunotherapy enjoying a high profile, interest in vaccines for NSCLC is emerging. The Roswell Park Institute in Buffalo, New York, announced in May that it will be the first US medical institution to offer a vaccine to treat lung cancer. The vaccine, called CIMAvax EGF, was developed by the Center for Molecular Immunology in Cuba. It acts by making circulating EGF immunogenic so that it is depleted by the immune system, thus depriving tumor cells of this growth factor. The vaccine will undergo clinical development for FDA approval in the US.^28,29

The therapeutic options regarding immunotherapy will increase when pembrolizumab, MEDI4673, tremelimumab, and atezolizumab are approved, which in addition to the developing small molecule inhibitors greatly increases opportunities to tailor therapies for patients.

Hand in hand with these newer agents in development is the search for improved biomarkers to identify appropriate patients, to detect disease earlier, and to elucidate the development of resistance. Progress is being made with regard to the status of PD-L1 on tumor cells as markers of the efficacy of immune checkpoint inhibitors.⁸A protein encoded by a cancer/testis gene calledAKAP4has recently been found to be a potential circulating biomarker for NSCLC, which could greatly facilitate very early detection of the disease.³⁰

Details of a potential new test for the development of resistance to first-generation anti-EGFR tyrosine kinase inhibitors were presented at ASCO 2015. By monitoring urinary circulating tumor DNA it was possible to detect acquisition of theEGFR T790Mresistance mutation. On further analysis, in some patients, urinaryEGFR T790Mcould be detected 1 to 3 months before progression was detected radiographically.³¹

References

1. US Food and Drug Administration. Approved drugs: nivolumab (Opdivo).http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm436566.htm. Accessed July 25, 2015.

2. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non—small cell lung cancer.N Engl J Med. 2015;373:123-135.

3. Luis Paz-Ares, Leora Horn, Hossein Borghaei,J Clin Oncol. 2015;33(suppl): Abstract LBA109.

4. Reuters. Merck files for FDA approval of Keytruda in lung cancer.

http://www.reuters.com/article/2015/04/19/us-merck-fda-lungcancer-idUSKBN0NA0HI20150419. Accessed July 25, 2015.

5. Garon EB, Rizvi N, Hui R, et al. Efficacy of pembrolizumab (pembro; MK-3475) and validation of PD-L1 expression as a biomarker in patients (pts) with non-small cell lung cancer (NSCLC): findings from KEYNOTE-001. Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 9109.

6. Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small-cell lung cancer.N Engl J Med. 2015;372(21):2018-2028.

7. Spigel DR, Chaft JE, Gettinger SN, et al. Clinical activity and safety from a phase II study (FIR) of MPDL3280A (anti-PDL1) in PD-L1—selected patients with non-small cell lung cancer (NSCLC). Presented at the ASCO Annual Meeting; June 1, 2015; Chicago, IL. Abstract 8028.

8. 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).J Clin Oncol. 2015;(suppl): Abstract 8010.

9. Antonia S, Goldberg SB, Balmanoukian A, et al. Phase 1b Study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody, in patients with advanced non-small cell lung cancer (NSCLC). Presented at: 2015 ASCO Annual Meeting, May 29-June 2, 2015. Poster 3014.

10. PR Newswire. Lilly statement on FDA advisory committee review of necitumumab.http://www.prnewswire.com/news-releases/lilly-statement-on-fda-advisory-committee-review-of-necitumumab-300111253.html. Accessed July 25, 2015.

11. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.Lancet Oncol. 2015;16:763-764.

12. Yoshida K, Yamada Y. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harboring EGFR mutations (JO25567): an open-label, randomized, multicenter, phase II study.Transl Lung Cancer Res. 2015;4(3):217-219.

13. Takeda. Takeda announces phase 3 MONET-A study evaluating motesanib (AMG 706) in patients with advanced non-squamous non-small cell lung cancer does not meet primary endpoint.https://www.takeda.com/news/2015/20150217_6909.html. Accessed July 25, 2015.

14. Sequist LV, Soria J-C, Goldman JW, et al. Rociletinib in EGFR-mutated non—small cell lung cancer.N Engl J Med. 2015;372:1700-1709.

15. Clovis Oncology. Rociletinib (CO-1686).http://clovisoncology.com/products-companion-diagnostics/rociletinib/. Accessed July 26, 2015.

16. Jänne PA, Yang J C-H, Kim D-W, et al. AZD9291 in EGFR inhibitor-resistant non-small cell lung cancer.N Engl J Med. 2015;372:1689-1699.

17. Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung8): an open-label randomised controlled phase 3 trial [published online ahead of print July 3, 2015].Lancet Oncol. . doi:10.1016/S1470-2045(15)00006-6.

18. US Food and Drug Administration. Approved drugs: afatinib.http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm. Accessed July 27, 2015.

19. Roche. Media release. Roche’s investigational medicine alectinib shrank tumours in nearly half of people with specific type of lung cancer.http://www.roche.com/media/store/releases/med-cor-2015-05-14.htm. Accessed July 27, 2015.

20. Gandhi L, Shaw AT, Gadgeel SM, et al. A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian population who had progressed on crizotinib (NP28761).J Clin Oncol. 2015;33(suppl): Abstract 8019.

21. Planchard D, Groen HJM, Kim TM, et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC).J Clin Oncol. 2015;33(suppl): Abstract 8006.

22.http://www.targetedonc.com/articles/breakthrough-designation-granted-to-brafmek-combo-for-braf-v600-nsclc. Accessed July 24, 2015.

23. Targeted Oncology. Breakthrough designation granted to BRAF/MEK combo for BRAF V600 NSCLC.http://www.targetedonc.com/articles/breakthrough-designation-granted-to-brafmek-combo-for-braf-v600-nsclc. Accessed July 25, 2015.

24. Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.Br J Cancer. 2014;110:55-62.

25. Pfizer. Pfizer receives US FDA Breakthrough therapy for XALKORI^®(crizotinib) for the treatment of patients with ROS1-positive non-small cell lung cancer.

http://www.pfizer.com/news/press-release/press-release-detail/pfizer_receives_u_s_fda_breakthrough_therapy_designation_for_xalkori_crizotinib_for_the_treatment_of_patients_with_ros1_positive_non_small_cell_lung_cancer. Accessed July 24, 2015.

26. Shaw AT, Ou SH, Bang Y-J, et al. Crizotinib in ROS1-rearranged non—small-cell lung cancer.N Engl J Med. 2015;372(7):683-684. .

27. Ramalingam SS, Blais N, Mazières J, et al. Smoking status to predict sensitivity to PARP inhibitor, veliparib, in patients with advanced NSCLC.J Clin Oncol. 2015;33(suppl): Abstract 8038.

28. Roswell Park Cancer Institute. Why There’s Renewed & Hopeful Interest in Cancer-Treatment Vaccines.

https://www.roswellpark.org/cancertalk/201506/why-there’s-renewed-hopeful-interest-cancer-treatment-vaccines. Accessed July 25, 2015.

29. Rodríguez PC, Rodríguez G, González G, et al. Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy.MEDICC Rev. 2010;12:17-23.

30. Gumireddy K, Li Anping, Chang DH, et al. AKAP4 is a circulating biomarker for non-small cell lung cancer.http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=3946&path%5B%5D=9105. Accessed July 25, 2015.

31. Husain H, Vibat CRT, Woodward B, et al. Kinetic monitoring of EGFR Exon 19 del, L858R, and T790M in urinary circulating tumor DNA predicts radiographic progression and response in patients with metastatic lung adenocarcinoma.J Clin Oncol. 2015;33(suppl): Abstract 8081.