I wanted to briefly discuss several very interesting abstracts that are going to be presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO) in gynecologic oncology, specifically the oral abstracts presented on Tuesday morning.
There are studies that analyze phase 1 clinical trials and include some interesting data. There is a very interesting section on surgery for gynecologic malignancies and one abstract in particular: a randomized phase 3 trial conducted by the Gynecologic Oncology Group. [This study] assessed the value of secondary surgical cytoreduction in patients with recurrent ovarian cancer and demonstrated no impact from surgery on survival.[1] That's going to be an interesting presentation.
There will be a discussions about robotics—a topic of great interest to clinicians—as well as neoadjuvant chemotherapy. There is also a very interesting abstract that looked at the potential benefits of adding bevacizumab to second-line chemotherapy in patients who had already received bevacizumab in the upfront, first-line setting.[2]This abstract demonstrated an improvement in progression-free survival with the addition of bevacizumab, despite the fact that the patients had had bevacizumab in the upfront setting.
This is going to be a very interesting session. For those of you interested in gynecologic malignancies, I would certainly encourage you to attend that session, or certainly, at a minimum, look at the abstracts that are actually available online.
The ASCO meeting is always very exciting. There are so many things going on in the gynecologic oncology sessions, which include not only the oral session I mentioned, but also poster sessions that should be very interesting, very provocative, and very important from the perspective of new developments, as well as the results of clinical trials. Thank you for your attention.
It is time for the annual meeting of the American Society of Clinical Oncology (ASCO), and for those of you going for the first time, you will enjoy a meeting of fantastic scientific quality. Plan ahead. Think of why you really want to go, and focus. Do not exhaust yourself; instead, pace yourself. I can say that as a veteran of many of these meetings. But clearly, ASCO, as well as the annual meeting of the European Society for Medical Oncology (ESMO), provide great breaking news and high-quality work. Enjoy yourselves.
I wanted to mention a few abstracts that caught my eye. In abstract 3509, Michael Geissler, MD, PhD, and colleagues[1] report on a very interesting study of triple chemotherapy with anti-EGFR, looking at combinations of a modified FOLFOXIRI regimen plus panitumumab versus FOLFOXIRI alone in chemotherapy-naive, front-line, nonresectable, RAS wild-type metastatic colorectal cancer patients.
It's a nice study design in terms of how you move the regimen forward. There was a 2-to-1 randomization of 96 patients. What really caught my eye was the extraordinary response rate in the combination arm: 85.7% versus 54.5% in the chemotherapy-alone arm.
It is fantastic that if we select patients appropriately, we can achieve response rates at this level. Clearly, this is a regimen that could be very effective in certain patient groups. There are also some subgroup analyses with relatively small numbers, which we should therefore treat with caution. But it's a study to watch for.
In another interesting abstract, 3507, Katherine Clifton, MD, and colleagues[2] have done a very nice study using a clever methodology to look at new copy number circulating DNA. They looked for driver mutations in a very large cohort of colorectal cancer patients; almost 5000 patients underwent molecular profiling with a plasma-based, next-generation sequencing assay.
The assay encompassed driver mutations like ROS1, RET, ALK, and some of the FGFreceptor fusions. In this well-designed study, they found 41 patients in whom they could detect DNA driver mutations. It was a huge effort and very well done; however, quite a small payback given the effort. Of course, there is no evidence as yet—at least in the abstract—as to whether those driver mutations were of any clinical use.
This raises the question of how much work is still to be done in terms of using next-generation sequencing in precision medicine. There is extraordinary potential for using gene sequencing, but can it actually be parlayed into significant, practical clinical benefit?
Another abstract that caught my eye was 3505, reported by an excellent Italian group with lead author Filippo Pietrantonio, MD.[3] This study addresses the question of maintenance chemotherapy in patients with RAS wild-type, unresectable, metastatic colorectal cancer. The patients received FOLFOX and panitumumab for eight cycles of induction therapy and then they were randomized to two different maintenance regimens: panitumumab alone or panitumumab plus infusion of 5-FU/leucovorin. They had 229 patients randomized equally across each arm. The study showed a benefit from maintenance with chemotherapy and panitumumab.
This is an area that still fascinates me. In the old days, we published a couple of papers in the Lancet from the United Kingdom in which we randomized patients who were responding or had stable disease to stop or continue chemotherapy until progression. In those rather old-fashioned studies, having a complete chemotherapy break did not interfere or reduce overall survival. And not surprisingly, it was associated with improved quality of life.
Of course, there have been more recent studies from Italy, France, and the Netherlands in which some form of de-intensified maintenance chemotherapy is associated with prolongation of progression-free survival. This is more or less what was shown here—that rather than just use panitumumab on its own, if one is de-intensifying chemotherapy, then use the infusion of 5-FU/leucovorin.
In our clinic, we tend to use capecitabine. And we tend to select patients for maintenance treatment who have a higher metastatic burden or tumor load on presentation; who present with relatively oligometastatic disease that is, for whatever reason, not technically ablatable or operable; and who have a good response to chemotherapy.
For the elderly, the frail, and those who have suffered toxicity with chemotherapy, we would give them a chemotherapy break and reintroduce chemotherapy on progression of disease.
In younger, fitter patients who are tolerating chemo and who had a big initial burden of disease, we would offer a maintenance treatment. A fluoropyrimidine and anti-EGFR inhibitor in RAS wild-type disease would seem entirely reasonable. But think about the possibility of a complete chemotherapy break for those who have more indolent disease and perhaps are less tolerant of chemotherapy.
In conclusion, enjoy the ASCO meeting. Please pick out those abstracts which interest you and tell us about them in the comments section.
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 EGFRmutation-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!
Do not miss the Plenary Session. We have been waiting for almost 7 years for the results of the TAILORx trial. We will wait no longer.
It was about 10 years ago that we first learned about and grew comfortable with the Oncotype DX® Breast Recurrence Score assay to identify which of our patients with node-negative, ER-positive tumors really needed chemotherapy.[1] Those with a low score really did not get any benefit. Conversely, those with a high score had huge benefit—much more than we had ever seen with chemotherapy in an ER-positive setting.
For all its power, Oncotype DX had an Achilles' heel, if you will. We had uncertainty about the benefits of chemotherapy in patients with an intermediate risk score. The point estimate for that group as a whole suggested that there was really not a benefit from chemo, but the confidence intervals included that same 2%-4% benefit that we might get from lumping everybody together. Thus, this was purpose of the TAILORx trial.
TAILORx[2] took patients with mid-range scores and randomized them to hormone therapy alone or hormone therapy with chemo to really tell us whether there is a benefit with chemo, and how much of a benefit. And hopefully can we get further nuanced as to who derives that benefit.
This trial enrolled almost 10,000 patients in aggregate. It shifted the boundaries of intermediate risk from the standard assay's cut points of 18 and 31; the trial used cut points of 11 and 25. This was done for two reasons. First, there was greater fear of undertreatment. Could we potentially lose the benefits we had lost by lumping everybody together if we selected patients for hormone therapy alone who really needed chemo? Also, pragmatically, the trial needed to randomize about 4500 patients in order to answer this question with only about a quarter of the patients in the intermediate-risk group by the original cut point. That was going to be difficult. By shifting the cut point, we estimated that about half of the patients would be in that group.
There will be lots of other news from the breast cancer session, but this is the one you want to make sure you get to. I am told by my colleague and the trial’s principal Investigator, Dr Joe Sparano, that the manuscript will be published concurrently with the presentation. That will allow us to get into more details than the short presentation will allow. Regardless of the results, this abstract is going to impact your practice. You are going to want to make sure you see it. I hope to see you there.
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