Better Practice: Improving first-line treatment against Stage 4 ALK-positive non-small cell lung cancer (NSCLC)

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Introduction

For patients with stage 4 lung adenocarcinoma, they should be tested for anaplastic lymphoma kinase (ALK) fusion oncogene rearrangements, which affects about 5% of non-small cell lung cancer (NSCLC).

This group of stage 4 lung cancer is highly sensitive to ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, ensartinib and lorlatinib).

Crizotinib

The first ALK inhibitor approved was crizotinib, when PROFILE 1014 study (crizotinib vs platinum doublet) showed increase progression free survival (10.9 vs 7 months).

Crizotinib is also an effective ROS1 inhibitor for an even smaller subgroup of stage 4 lung cancer (NSCLC with ROS1 mutation positive).

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Crizotinib’s PROFILE 1014 (first line crizotinib); overall survival and progression free survival results (BJ Solomon, 2014)

Ceritinib

Next ALK inhibitor approved was ceritinib, based on the results from ASCENT-4 study comparing ceritinib against platinum doublets.

There is increase in progression free survival (16.6 with ceritinib vs 8.1 months with platinum doublets).

Two year overall survival rates were 70∙6% in the ceritinib group and 58∙2% in the chemotherapy group. Average/ median overall survival data is not available yet as patients are living longer.

Interestingly, there was some activity in brain metastasis, although presence of baseline brain metastases is still an adverse prognostic factor.

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Ceritinib’s ASCENT-4 (first line NSCLC); progression free survival (PFS)
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Ceritinib’s ASCENT-4 (first line NSCLC); overall survival (OS)

Better practice

Alectinib

Phase III ALEX trial comparing alectinib with crizotinib as first-line treatment against stage 4 ALK-positive non-small cell lung cancer (NSCLC) showed:

  • Average/ median progression-free survival (PFS) of 34.8 and 10.9 months for patients treated with alectinib and crizotinib, respectively.
  • Alectinib significantly reduced risk of disease progression/death by 57%
  • Overall survival data is still immature in this update

Three times improvement in progression-free survival (PFS) when compared with current standard of care/ standard treatment is very impressive.

Does it work as well in patient with brain metastasis?

  • In brain metastasis patients, average/ median progressive-free survival (PFS) was 27.7m in alectinib vs 7.4m in crizotinib; reducing disease progression risk by 65%

With promising results from ALEX trial, I think it will soon (if not already) be the standard of care and first line treatment in advanced ALK-positive non-small cell lung cancer (NSCLC).

Second line usage of alectinib after failure of crizotinib were also effective. In phase 3 ALUR trial, the progression free survival (PFS) were 7.1 vs 1.6 months with alectinib and chemotherapy, respectively

Does better treatment means stronger treatment and more side effects?

  • Surprisingly, side effects that leads to treatment interruption or dose reduction were lower in alectinib when compared with crizotinib.
  • Proportions discontinuation of treatment due to side effects are equal for both treatment ~ 13%

I remembered one patient who had brain metastasis was started on this medication. She was getting it for free last time when alectinib was not registered yet for use in Malaysia.

She tolerated the medication well. I hope she will fare as good, if not better, than the results above.

Coming soon…

Brigatinib

ALTA-1L trial (phase 3, brigatinib vs crizotinib) in patients with ALK-positive advanced NSCLC, was reported to have met primary endpoint of the study.

A phase II study of 222 patients with crizotinib-refractory, ALK-positive NSCLC demonstrated PFS of 9.2 and 12.9 months among those receiving a lower and higher dose of brigatinib.

Ensartinib

Ensartinib is a multikinase inhibitors (ALK, MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK).

In phase 1/II study, it had been proven to be effective in CNS metastasis, just like alectinib (above).

It’s currently further evaluated in the ongoing phase III eXalt3 trial (ensartinib vs crizotinib).

IMHO, the comparator arm should be against alectinib instead of crizotinib (since almost all newer ALK inhibitors is better than crizotinib, plus  crizotinib was totally ineffective in CNS metastasis anyway).

Lorlatinib

Lorlatinib wants to be considered as 3rd generation ALK/ ROS1 tyrosine kinase inhibitors due it’s potency on CNS metastasis but I think it’s easier to group it together as second generation with brigatinib and ensartinib

It’s and its use after failure of 1 or > 1 lines of ALK inhibitors after development of resistance.

Finally

I think alectinib will be my first line treatment for ALK mutated NSCLC if patients can afford such expensive treatment.

I do hope the price for alectinib can come down more in order for more patients to benefit from this treatment.

As for 2nd generation ALK inhibitors, I think the competition will be to see who will take the second line setting (haha!) spot.

It’s still too early to see if longer PFS can be seen from 2nd generation ALK inhibitors as compared with alectinib (again) PFS of 7.1 months (ALUR trial).

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