TKIs Competing for Frontline Therapy in ALK+ NSCLC

Targeted Therapies in Oncology, July 2016, Volume 5, Issue 5

Deciding the sequencing order of therapies for patients with ALK-positive non–small cell lung cancer (NSCLC) is a challenge, as new information on next-generation tyrosine kinase inhibitors (TKIs) comes to light, says Robert Doebele, MD, PhD. Testing for ALK translocations can help to determine which therapies NSCLC patients should be receiving, but questions regarding the sequencing of ALK inhibitors still remain.

Robert Doebele, MD, PhD

Deciding the sequencing order of therapies for patients with ALK-positive non—small cell lung cancer (NSCLC) is a challenge, as new information on next-generation tyrosine kinase inhibitors (TKIs) comes to light, says Robert Doebele, MD, PhD. Testing for ALK translocations can help to determine which therapies NSCLC patients should be receiving, but questions regarding the sequencing of ALK inhibitors still remain.

Options and outcomes for various TKIs were discussed during the Physicians’ Education Resource (PER®) seminar “Oncogenic Tumor Board in NSCLC: Targeting Driver Mutations to Maximize Therapeutic Outcomes,” which took place during the 2016 ASCO Annual Meeting in Chicago.

The seminar emphasized that treatment options for ALK+ NSCLC patients are changing so quickly that options for frontline and later treatments may be very different in the future. “This is an evolving field,” said panelist Jonathan Riess, MD, MS, assistant professor of Medicine at the UC Davis Comprehensive Cancer Center. “In a year there may be a different answer.”


A large multicenter study gathered characteristics of 273 patients diagnosed with ALK+ NSCLC.1The median age of ALK+ NSCLC diagnosis was 67 years (range, 58-72) and there was an even divide between males and females. Thirty-three percent of the participants were heavy smokers and another 33% were nonsmokers. Eighty-eight percent of the patients had stage IV NSCLC, most of which were adenocarcinomas.

Testing for genetic mutations and translocations helps to target therapies to the specific mutation, and while ALK is identifiable in early-stage cancer patients it is mostly tested for in late-stage disease only. Testing in early-stage disease is currently being explored to test if TKIs have a role in earlier disease settings, said Doebele, associate professor of the Division of Medical Oncology at the University of Colorado Anschutz Medical Campus.


Once a patient has been diagnosed with an ALK translocation, the most common treatment is currently the first-generation TKI crizotinib (Xalkori), which showed significant improvement in overall response rate (ORR), progression-free survival (PFS), and toxicity over chemotherapy in both first- and second-line settings. In the Pfizer 1014 trial, the ORR for front-line crizotinib was 75% versus 45% for chemotherapy.2PFS for patients in the crizotinib arm was 10.9 months and 7 months for the chemotherapy group.

Doebele suggested platinum pemetrexed (Alimta) as the chemotherapy regimen for ALK+ NSCLC patients who have failed TKI treatments or have run out of TKI options. “There seems to be exquisite sensitivity in ALK+ to pemetrexed-based therapy.”

The target enzyme thymidylate synthase (TS) is incredibly low in ALK+ cancers, which may explain the sensitivity of ALK+ NSCLC cancer patients to pemetrexed, added seminar leader David Gandara, MD, director of Thoracic Oncology, UC Davis Comprehensive Cancer Center.

For patients with treatment-naïve ALK+ NSCLC, the J-ALEX study compared treatment of first-line alectinib (Alecensa) with crizotinib. In data for the phase III trial presented at the 2016 ASCO Annual Meeting, the crizotinib arm had a median PFS of 10.2 months (95% CI, 8.2-12.0), and the median PFS was not reached in the alectinib arm (95% CI, 20.3-not estimated).3Alectinib already seemed to show a preliminary benefit over crizotinib.

Several of the second-generation ALK inhibitors could potentially replace crizotinib as first-line therapy. In treatment-naïve patients, crizotinib showed an ORR of 74% compared with 72%, 94%, and 100% from ceritinib, alectinib, and brigatinib, respectively. The median PFS was 10.9 months for patients on crizotinib, 18.4 months for ceritinib, more than 29 months for alectinib, and the median PFS was not reached for patients on brigatinib.4,5,6

For patients who have already shown resistance to ALK inhibitors, the second-generation drugs showed ORRs of 56% for ceritinib, 50% for alectinib, and 69% for brigatinib. The median PFS for patients on ceritinib was 6.9 months, 8.9 months for alectinib, and 13.4 months for brigatinib.


Crizotinib, in comparison with some of the next-generation inhibitors, does not show central nervous system (CNS) penetration, which is significant, as most metastases develop in the brain for patients with ALK+ NSCLC.

Doebele suggested that a newly diagnosed ALK+ NSCLC patient with brain metastases could be treated with a TKI that has shown antitumor activity in the brain as well, such as with alectinib or brigatinib, as a frontline therapy instead of treatment with crizotinib plus radiation.

“CNS penetration may be the game changer for the next generation [of TKIs],” Doebele said.

CNS activity is hard to compare between the various TKIs due to various results criteria. However, brigatinib has shown a comparatively longer duration of response for CNS activity than alectinib, with 18.9 months versus 10.3 months.


A great majority of the audience members believed that patients should be re-biopsied upon disease progression. A biopsy at disease progression would help with selecting therapies that target specific resistance mutations, such as MET, which has shown resistance to alectinib and ceritinib but sensitivity to crizotinib.

The resistances and sensitivities of the various inhibitors to specific mutations in ALK+ NSCLC patients are still being explored, especially for newer inhibitors brigatinib and third-generation agent lorlatinib. Identifying the patient’s muta¬tions could determine which drug would be best based on its individual sensitivities.

Doebele, however, argued that it is okay if it is not possible to attain a new biopsy. In a study of NSCLC patients on ceritinib, responses were even seen amongst patients who did not haveALKmutations or gene amplification,7emphasizing that a biopsy to test forALKmutations may not be imperative.

“Even when we can’t detect a resistance mutation there may be benefit to these next generation inhibitors. So if it’s unsafe to biopsy the patient because they’re on Plavix and can’t come off or you can’t access the site or blood-based testing doesn’t reveal anything, it is okay to move on and the response rate is still good in those patients,” Doebele said.


  1. Guérin A, Sasane M, Zhang J, et al. ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer.Cancer Epidemiol.2015;39(3):307-12.
  2. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer.N Engl J Med.2014;371(23):2167-2177.
  3. Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor naive ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study.J Clin Oncol34, 2016 (suppl; abstr 9008).
  4. MKim DW, Mehra R, Tan DS, et al. Activity and safety of ceritinib in patients with ALK-rear¬ranged non-small0cell lung cancer (ASCEND-1): updated results from the multicenter, open-label, phase 1 trial.Lancet Oncol.2016; 17(4): 452-463.
  5. Ou SH, Ahn JS, De Petris L, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small- Cell Lung Cancer: A Phase II Global Study.J Clin Oncol.2016; 34(7):661-668.
  6. Camidge DR, Bazhenova L, Salgia R, et al. Safety and efficacy of brigatinib (AP26113) in advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).J Clin Oncol33, 2015 (suppl; abstr 8062).
  7. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer.N Engl J Med.2014;370(13):1189-97.