Bazhenova Compares Frontline ALK Inhibitors for ALK+ NSCLC

Lyudmila Bazhenova, MD

Lyudmila Bazhenova, MD, a professor of Medicine, Moores Cancer Center. University of California San Diego Health in La Jolla, CA, led a peer discussion about the frontline treatment options for a middle-aged male patient with ALK-positive non–small cell lung cancer (NSCLC).

Targeted OncologyTM: What are the systemic frontline treatment options for this patient?

BAZHENOVA: Currently, for patients with ALK-fused non– small cell lung cancer [NSCLC], we have 4 drugs that are in the National Comprehensive Cancer Network guidelines and FDA-approved for first line. So, the original drug was crizotinib [Xalkori], based on PROFILE 1014 [NCT01154140], [which was] compared [with] platinum/pemetrexed [by] investigator-determined progression-free survival [PFS].¹ All 4 studies had a different follow-up period, at least at the time of the first report. Crizotinib had about 10.9 months PFS. Then the second drug that came to market was ceritinib [Zykadia], [in the] ASCEND trial [NCT02336451],² also compared [with] platinum/pemetrexed, [there was] similar PFS end point by investigator [assessment]. The PFS here was bigger, at about 16.6 months.

Next came alectinib [Alecensa] through the ALEX trial [NCT02075840],3 and both ALEX as well as ALTA-1L [NCT02737501],⁴ which is the brigatinib [Alunbrig] trial, compared alectinib [with] crizotinib. Both of them showed improvement in median PFS. The PFS determination was slightly different. For the ALEX it was investigator determined, and for the ALTA, it was blinded independent review committee [BIRC] determined. The ALEX showed 34.8 months PFS,³ and then ALTA-1L, by BIRC, showed 24 months PFS.^4,5 Response rates were very similar across [the 4 trials—74% to 83%]. That’s what we’d expect with ALK-fused cancer. All tyrosine kinase inhibitors [TKIs] generally have a fairly decent systemic response. What’s also interesting, and that’s what’s building up on the point of CNS penetrance, the later drugs definitely have a high incidence of intracranial response rate. We don’t have the median PFS reported yet for patients with baseline brain metastases. The hazard ratio [HR] for ALEX for patients with brain metastases was 0.4,6 and the HR for ALTA for the patients with brains metastases was 0.24.⁴ Both were statistically significant [P < .0001].^4-6

[On] May 20, 2020, brigatinib was approved for ALK-mutant metastatic NSCLC, regardless of the line of therapy.⁷ Before that, brigatinib approval was for people who failed crizotinib, and then this year it gained approval for the newly diagnosed untreated patients.

Also, during this ASCO [American Society of Clinical Oncology Annual Meeting], we had a long-term update of the ALEX trial with almost 50 months follow-up.⁸ The ALEX trial showed improvement in overall survival [OS] when patients received alectinib versus crizotinib. The numbers, in my opinion, are quite stunning. The overall 5-year OS [rates] for our ALK-positive patients were 62.5% in the alectinib arm and about 45.5% in the crizotinib arm [HR, 0.67; 95% CI, 0.46- 0.98; P = .0376].

Subgroup analysis, also from that ASCO presentation, [was] similar to what we saw at the time of the original presentation. All the subgroups benefited. Some of the confidence intervals did cross unity, but at least the medians were clearly toward alectinib. And the HR again in patients with CNS disease at baseline was 0.58 if they had it [log-rank P = .0477] and 0.76 if they didn’t [log-rank P = .2851].

Next is the ALEX trial looking at systemic PFS in the patients with and without CNS metastasis. The benefit was relatively more substantial if the patient had a CNS metastasis [median PFS, not reached (NR) with alectinib vs 7.4 months with crizotinib; HR, 0.40; 95% CI, 0.25-0.64; P < .0001] because crizotinib did poorly in that subgroup compared [with] where you see no baseline CNS metastasis, then crizotinib performed a bit better [median PFS, NR vs 14.8 months; HR, 0.51; 95% CI, 0.33-0.80; P = .0024]. The alectinib arm, if you do like cross Kaplan-Meier comparisons, the patients did somewhat similarly if they did or did not have baseline CNS metastasis. But the HR is different just because of the crizotinib poor performance in baseline CNS metastasis. We know that because crizotinib does have CNS penetration, but it is not perfect.

Many of us decide not to give radiation [to] patients with CNS metastases, and you can see [in these results] that if you did not give radiation, the crizotinib arm performed poorly. Alectinib showed improvement in PFS in both of those [groups] if you did have or did not have radiation to the brain.⁶

Then would you suggest radiation of the CNS metastases in this patient?

I think the caveat in looking at the survival curves here is just the numbers are very small. We don’t know the answer to the question, Should we radiate the patients or should we not? There’s a clinical trial going [in] Australia, a randomized, prospective clinical trial that is to answer exactly the same question. And there was a retrospective analysis, an EGFR paper, not an ALK paper, showing that radiation for patients showed maybe an improvement in the OS. But this is a retrospective analysis and, because radiation wasn’t randomized, it can be biased.

What I do [is start the patient] on the TKI and then do MRI in 6 weeks. If everything went away, good, but if [CNS metastases] are still there, even though they shrank, I would recommend doing consolidative radiation for those brain metastases that are still there after the radiation.

Brigatinib is the newest of these 4 ALK inhibitors. What data support its use in the frontline setting?

The ALTA-1L trial is a recent development. ALTA-1L [included] 275 patients randomized 1:1 [who had] stage IV ALK-mutant NSCLC. Prior chemotherapy was allowed, compared [with] the ALEX trials where they didn’t, and then they randomized patients to brigatinib at a standard FDA-approved dose versus crizotinib, treated until progression or intolerable toxicity. The primary end point of this study was PFS by BIRC. Then they stratified them also by brain metastasis and by prior chemotherapy use.

The HR for disease progression by the blinded independent review was 0.49 [95% CI, 0.35-0.68; log-rank P < .0001], by the investigators review, 0.43 [95% CI, 0.31-0.61; log-rank P < .0001]. For the investigator [assessment], the [median] PFS was 29.4 months [for brigatinib], and by BIRC it was 24.0 months. And crizotinib performed somewhat [similarly], at 9.2 months for the investigator [assessment] and 11.0 months for BIRC.⁵

Similar to the alectinib trial, the forest plot continued to show that brigatinib outperformed crizotinib, regardless of presence or absence of brain metastases and prior chemotherapy. If you look at the HRs for prior chemotherapy, they’re quite similar, 0.44 [with prior chemotherapy] and 0.52 [without]. But HRs for brain metastases, if [the patient had] brain metastases, the differential between brigatinib and crizotinib was much better than if you did not have brain metastases.

So, if [the patient had] brain metastases [at baseline], further curves are separating. The HR here is 0.25 [95% CI, 0.14-0.46; log-rank P < .0001], which is significant. For the patients without brain metastases, the curves are still separating, but the HR here is 0.65 [95% CI, 0.44-0.97; log-rank P = .0298].

As we saw in prior TKI to TKI studies, the overall response rates [ORRs] were similar [at 71% with brigatinib versus 60% with crizotinib]. We don’t know the significance of that, but brigatinib had deeper responses compared [with] crizotinib. But there are some emerging data that the absolute response maybe matters in [terms of] the PFS, but that was not the point of this study.

Remember in the ALEX trial, we have a 5-year OS. Here [in the ALTA-1L trial], we don’t. We are not yet at the 5-year mark, and so far we have not seen OS benefit. The caveat in interpreting OS curves here is patients who were on the crizotinib arm, since brigatinib was commercially available, many of them crossed over to brigatinib therapy—about 44%. Then if you have progressed on crizotinib and you moved to brigatinib, your PFS was 15.6 months, which is, to the decimal, identical to the PFS of brigatinib plus crizotinib in the ALTA study, which was 15.9 months. The ORR for those patients who went from crizotinib to brigatinib was 54%.

What is the safety profile for these agents, and how do they compare?

Both of those medications are safe. Dose discontinuation due to adverse events is low [11% with alectinib and 13% with brigatinib]. There is a slight difference between them [in terms of the safety profile]; with brigatinib, that drug causes increased creatine phosphokinase [CPK], usually not associated with any kind of symptoms. But the way the protocol was written, dose reductions were required for increased CPK. Other things we see [are increased] lipase, amylase levels— usually not associated with pancreatitis, just laboratory abnormality. And then for the alectinib, you see hyperbilirubinemia, [increased] aspartate aminotransferase levels, liver function tests, and pneumonitis.

How do you decide which of these agents, alectinib or brigatinib, to use in the frontline setting?

That’s the million-dollar question, to be honest with you. I have a lot of experience with brigatinib. I think when the data first came out, I was, like, “Those drugs are similar,” and then I was already using alectinib and I was, like, “Why would I switch?”

I think now the more I dive into the data and the more I kind of dissect the data, I am intrigued by the difference in HR in the [patients with brain metastases]. I’m starting to lean toward using brigatinib for patients with brain metastases and doing alectinib for patients without. But there is no way for us to truly decide.

I think there are many examples in oncology where I am familiar with the drug, and when the new drug came to market, I was, like, “Why would I switch? I already know the previous drug. It doesn’t bother me, doesn’t appear to be different.” So I think familiarity does play a significant role, and I would not be correct in telling you that everybody has to switch to brigatinib because it’s a better drug. We don’t have that evidence. I think it’s a matter of slicing the data and doing subset analysis and [gaining] familiarity. I think if you are familiar with alectinib, it’s not wrong to keep using alectinib. I’m telling you my opinion. I’m not claiming to be the know-it-all and only correct opinion. But it’s a good question.

_References:

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_{2. Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non–small-cell lung cancer (ASCEND- 4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-929. doi:10.1016/S0140-6736(17)30123-X}

_{3. Peters S, Camidge DR, Shaw AT, et al; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. 2017;377(9):829-838. doi:10.1056/NEJMoa1704795}

_{4. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in advanced ALK inhibitor-naive ALK-positive non–small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. J Clin Oncol. Published online August 11, 2020. doi:10.1200/JCO.20.00505}

_{5. Camidge R, Kim HR, Ahn MJ, et al. Brigatinib vs crizotinib in patients with ALK inhibitor-naïve advanced ALK+ NSCLC: updated results from the phase III ALTA-1L trial. Ann Oncol. 2019;30(suppl 9):ix183-ix202. doi:10.1093/annonc/mdz446}

_{6. Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non–small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018;29(11):2214-2222. doi:10.1093/ annonc/mdy405}

_{7. FDA approves brigatinib for ALK-positive metastatic NSCLC. News release. FDA. May 22, 2020. Accessed September 14, 2020. https://bit.ly/35trc3}

_{8. Peters S, Mok TSK, Gadgeel SM, et al. Updated overall survival (OS) and safety data from the randomized, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated advanced ALK+ NSCLC. J Clin Oncol. 2020;38(suppl 15):9518. doi:10.1200/JCO.2020.38.15_suppl.9518}