Top 5 Lung Cancer Presentations at ASCO 2018

H. Jack West, MD

Disclosures

May 30, 2018

With the American Society of Clinical Oncology (ASCO) Annual Meeting right upon us and so much to see, we now need to prioritize the top abstracts to see with the limited time and attention that we have to spend at the meeting. To help with that, I want to offer my top 5 recommended abstracts in advanced non–small cell lung cancer (NSCLC) in a year that will provide several practice-changing findings.

KEYNOTE-042

The plenary presentation on Sunday, June 3, by Gilberto Lopes, MD, MBA, of the KEYNOTE-042 trial (LBA4), has to top the list for advanced NSCLC.[1] We know from a prior press release[2] that the trial is positive, and the fact that it will be featured in the plenary session highlights that this is a clinically important trial.

KEYNOTE-042 directly compares pembrolizumab (pembro) monotherapy versus histology-appropriate doublet chemotherapy for either squamous or non-squamous NSCLC in patients with tumor PD-L1 expression of ≥ 1%. This makes it very similar in design to the earlier KEYNOTE-024 trial, which also directly compared pembro with histology-appropriate doublet chemotherapy, but only in the smaller subset of patients with PD-L1 of ≥ 50%, in which first-line pembro was far superior in efficacy[3] and has become a standard of care for these patients. The press release on KEYNOTE-04[2] notes an improvement in overall survival (OS), but what we'll need to see is whether the benefit is really compelling for the patients with lower PD-L1.

We need to see whether the benefit is really compelling for the patients with lower PD-L1.

Because we know that the patients with a high level of PD-L1 of > 50% do far better with pembro than with doublet chemotherapy, the leading question with KEYNOTE-042 will be whether the patients with lower tumor PD-L1 expression—looking at cut-offs of 1%, 20%, and 50%—all clearly achieve a striking efficacy benefit with pembro; or whether this trial is positive overall because the entire study population is being driven by the benefit seen in patients with higher PD-L1, while those with lower level tumor PD-L1 expression may not do as well. This will be an important distinction, because in addition to the long-standing option of chemo followed by second-line immunotherapy, we also have a growing number of options of first-line chemo/immunotherapy, including the recently reported KEYNOTE-189 trial,[4] which showed a highly significant improvement in OS with a combination of cisplatin or carboplatin with pemetrexed and pembrolizumab compared against the same chemo alone. This means we have competing options of immunotherapy alone or with chemotherapy, at least for patients with non-squamous NSCLC, and some of our further abstracts on this top 5 list create the same open question for patients with advanced squamous NSCLC.

KEYNOTE-407

Second on the list is KEYNOTE-407, presented by Luis Paz-Ares, MD (A#105),[5] and featured at the Clinical Science Symposium on Saturday, June 2.

This trial evaluates carbo/paclitaxel (pac) or nab-paclitaxel (nab-pac) with either placebo or chemo alone in patients with advanced squamous NSCLC, regardless of the level of tumor PD-L1 expression. A prior press release[6] highlighted a significant improvement in objective response rate (ORR), while the recently released ASCO abstract clarifies that it is actually 23% higher in the patients on chemo/immunotherapy compared with the chemo/placebo arm (58.4% vs 35%; P = .0004).

While this was already impressive enough to lead to discussion of this regimen's clinical relevance, the latest press release[7] announces a significant improvement in progression-free survival (PFS) and OS as well. We should see these exciting results at ASCO. And now with a significant improvement in ORR, PFS, and OS, we should expect a timely FDA approval of this regimen for advanced squamous NSCLC, regardless of tumor PD-L1 expression, which will make it a new compelling standard vying with pembro monotherapy in eligible patients as a leading option.

IMpower131

The third presentation in my top 5, the IMpower131 trial, also focuses on the same advanced squamous NSCLC population and is being presented by Robert M. Jotte, MD, PhD, in the oral abstracts session on Monday, June 4 (A#9000).[8] This study also evaluates carbo with pac or nab-pac, alone or combined with atezolizumab (atezo). A press release about this trial has also reported that we'll see a significant improvement in PFS with carbo/nab-pac and atezo.[9] While that's encouraging, the key issue is that the real comparison isn't with the platinum doublet chemo alone, as in the trial, but with the chemo/pembro combination in KEYNOTE-407, especially with the newly reported improvement in OS as well as PFS with carbo/nab-pac/pembro, which has upped the ante greatly in this setting. Moreover, pembro will have an advantage from the momentum of the positive results reported in the plenary presentation of KEYNOTE-042 and the recently reported results of KEYNOTE-189 in the non-squamous NSCLC population, an array of highly impressive and consistent results.

CheckMate-227

Another potential option will be introduced with new results from CheckMate-227, with Hossein Borghaei, DO, presenting results on patients with tumor PD-L1 expression < 1% in the oral abstracts session on Monday, June 4 (A#9000).[10]

There are many aspects to this complex trial, but this analysis will focus on a comparison of nivolumab (nivo) with concurrent chemotherapy doublet compared with chemotherapy in patients with either advanced squamous or non-squamous NSCLC. The abstract reports an improvement in PFS with the nivo/chemo combination (HR 0.74); interestingly, the difference was far more pronounced in favor of the chemo/immunotherapy arm for the non-squamous population (HR 0.68), with barely any difference in patients with squamous NSCLC (HR 0.92). I think that's going to be a very limiting issue in the squamous population, particularly when we have several other options, as I described above, that seem to be far more impressive in the benefits they confer.

Targeted Therapy

Alas, not every presentation at ASCO is about immunotherapy, and one about targeted therapy in advanced NSCLC that deserves a place on the list is ARCHER 1050, being presented by Tony Mok, MD, in the same oral abstract session on Monday, June 4 (A#9004).[11] This trial of the second-generation EGFR oral inhibitor dacomitinib versus gefitinib in patients with advanced EGFR mutation-positive patients without brain metastases has already been reported as demonstrating an impressively greater PFS with dacomitinib (14.7 vs 9.2 months, P <.0001),[12] but we hadn't yet seen OS results. Toxicity issues with this agent were quite significant, potentially limiting the broad utility of this drug. Dr Mok will now be reporting OS results from this trial, which are being presented in a few permutations and are equivocal in terms of whether they would be considered statistically significant. Nevertheless, the findings may be enough to lead some to change their view about whether there could be a role for dacomitinib in advanced NSCLC. Of note, this is a setting where we now have osimertinib, a third-generation inhibitor just approved as first-line therapy for patients with a common, activating EGFR mutation.[13] But with dacomitinib coming in with a PFS of nearly 15 months, and an arguably significant improvement in OS that approaches a median of 3 years—while still preserving the option of osimertinib as a second-line therapy for patients who progress with a T790M acquired resistance mutation—we will have more fodder for discussion about the potential value of sequencing EGFR inhibitors after starting with dacomitinib, provided that oncologists and patients can accept the toxicity challenges of this agent.

Honorable Mention

Finally, my honorable mention that doesn't quite make this list is a Japanese study, NEJ026, comparing erlotinib/bevacizumab with erlotinib alone in first-line EGFR mutation-positive disease, and presented by Naoki Furuya, MD, PhD, also in the Monday, June 4, oral abstract session for advanced NSCLC (A#9006).[14]

We learn from the abstract that this trial corroborates that bevacizumab significantly improves PFS, coming in at a median of about 17 months, but I'm not sure if this will bubble up to change practice compared with other options like osimertinib or, as I noted above, possibly dacomitinib, without the infusions and cost required with bevacizumab.

I hope to see you in Chicago if you're attending ASCO 2018. If not, please follow the commentary and information coming out from the conference. We can already see that this will prove to be a year with plenty of practice-changing results in advanced NSCLC, as well as other cancer treatment settings. More soon!

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