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Musings of a Cancer Doctor

Wide-ranging views and perspective from George W. Sledge, Jr., MD

Friday, June 19, 2020

ASCO 2020: Breast Cancer & Meeting From Afar

By George W. Sledge, Jr., MD

The American Society of Clinical Oncology's 2020 meeting was held, not in Chicago, but virtually, the citizens of Oncoville scattered around the world like refugees from some vast cataclysm or natural disaster. No, wait. That's not a metaphor. There actually was a natural disaster. COVID-19 haunted the halls of McCormick Place, and the rest of us avoided it, well, like the plague (a phrase that has taken on new meaning).

I take notes at ASCO and similar meetings by tweeting. I can then go back later and see what thoughts I had in the moment about a particular study. It requires a certain discipline that I might not otherwise be capable of, and it keeps me busy when my mind might otherwise wander. Halfway through the meeting, I tweeted a brief list (brief because of Twitter's character limit) of pros and cons for the virtual meeting; of all my tweets at the meeting, it got the most responses. If you are not my Twitter follower, let me repeat them for you.

On the pro side, the virtual meeting meant that there actually was an ASCO Annual Meeting. I can't thank the ASCO staff enough for pulling this off on such relatively short notice. I'm sure it involved a Herculean effort on their part. Maintaining the continuity of the world's premiere cancer meeting in the midst of a pandemic is reason for celebration and gratitude.

The talks themselves had parallel video and Power Points. I appreciated this; getting to hear the speaker is one thing, but getting to linger over the data is another, and the virtual meetings' format allowed for both. Also—and this was an unexpected bonus—I could always pause watching and eat dinner between presentations. It was definitely more relaxed in that sense, and several responses to my tweet pointed out the calming nature of not having to sprint across the convention center between talks at different venues. Like any of my friends needed the exercise.

But for me, the cons outweighed the pros. The video presentations only worked about half the time. One reply to this tweet said "You must have special pull. Mine only worked 30% of the time." I assumed this was a bandwidth issue. Over 40,000 people visited the virtual meeting, and I suspect this overloaded the system. This was an irritant, if a minor one, as I could switch to the slide set. I suspect that the technology will continue to improve in future years.

There were two larger issues. First, it felt like homework. I don't know any other way to put it. When I sit in the audience at ASCO, and some great data pops up on the screen, there is a current of excitement that flows through the convention hall. That electric sensation disappeared when I plodded through breast cancer talks at home. It was simply less fun. Not ASCO's fault, nor the presenters, but there it is.

But the biggest issue for me was that I miss my friends. Societies socialize. They bring together diverse groups from around the globe, people we haven't seen during the year, and we get to hang out and talk. Sometimes that talking is about family and friends, sometimes about oncopolitics, and sometimes it involves how to interpret the talk we've just heard and how to apply the results to the next trial we're designing or the patient we'll see on Monday morning in clinic. I cannot count the number of times that a research project began in casual conversation in the lobby of the Chicago Hilton or outside Hall D.

ASCO is also an efficient place to hold meetings. My schedule often involves 15 or 20 side meetings. They're not all worthwhile. Most meetings don't amount to much in the long run: you can't meeting your way to a cure. But collectively, they always added something to my knowledge and forwarded my research agenda. And that disappeared along with the handshakes and hugs, another COVID casualty.

All of which is a long-winded way of saying I hope this isn't the permanent way we do the ASCO Annual Meeting. I think having a virtual meeting in parallel to the "real" meeting has value, and I trust it will continue, for the benefit of our many colleagues who cannot attend. But I want to be back in Chicago, as long as I and my colleagues all receive an effective coronavirus vaccine.

Breast Cancer at ASCO

As for breast cancer at the meeting, there are annual meetings which represent great leaps forward, with bold paradigmatic shifts that fundamentally alter how we understand or treat the disease. Think of these as discovering a new continent. And there are years which can best be characterized as "filling the empty holes on the map." This was, by and large, the latter.

One breast cancer presentation made it to the Plenary session. Seema Khan presented the ECOG/ACRIN group's E2108 trial. By way of Conflict of Interest statement, I'm the senior author on this presentation. This trial addressed, and perhaps answered, the question of "what do we do with the breast when a patient presents with metastatic disease. Patients with stage IV disease received several months of initial systemic therapy and were then randomized to either local-regional therapy or to no local-regional therapy and continued systemic therapy. With fairly long follow-up, there was no difference in overall survival.

Two previous trials from Turkey and India had addressed the same question, and another similar trial is ongoing, so the final answer might not be in yet. Local-regional therapy in the setting of stage IV disease can have objectives other than overall survival, such as preventing catastrophic local failure and relieving psychological stress. But for the moment I do not think any physician should walk into a room with a patient and claim that local-regional therapy will prolong life by so much as a day.

Unlike many trials at the annual meeting, there was no nifty new biologic tested nor any deep pockets of Big Pharma support pushing E2108 to conclusion. The trial was a labor of love, ably designed and led by Northwestern's Dr. Seema Khan. It was the sort of trial that the National Clinical Trials Network is well-suited to conduct, answering an important question that would otherwise remain occult.

HER2-positive breast cancer was an important focus for ASCO 2020. Certainly, the most important of the trials presented was HER2CLIMB, a trial examining the highly HER2-selective receptor tyrosine kinas inhibitor tucatinib. This trial was important for two reasons, one of which was a game-changer for a major unmet medical need. First, the trial (which randomized patients to receive trastuzumab and capecitabine with or without tucatinib) had previously shown an overall improvement in progression-free and overall survival.

But what made HER2CLIMB special was its focus on brain metastasis. HER2-positive breast cancer is trophic for the central nervous system, yet the vast majority of trials conducted in this disease actively excluded patients with CNS metastasis, or required treated, stable or responding brain metastasis as entry criteria. In contrast, HER2CLIMB allowed patients with both treated and untreated brain metastasis (though it excluded leptomeningeal disease), and thereby allowed us to evaluate the effect of tucatinib on the brain. Both CNS-PFS (progression-free survival in patients with brain metastasis) and overall survival in patients with brain metastasis favored the tucatinib arm of the trial, with a 1-year landmark analysis showing a median survival of 18.1 versus 12 months, and CNS-PFS of 70.1 percent versus 46.7 percent.

This is not to say that we have solved the problem of brain metastasis in HER2-positive disease. But tucatinib represents a real step forward, and the willingness of the study sponsors to tackle this huge unmet medical need is laudable. This is a drug that I suspect will rapidly progress from the later line setting of this trial to a more frontline metastatic setting or the (neo)adjuvant setting. Perhaps more importantly, future trials in the advanced disease setting will now be judged against a drug with efficacy in the central nervous system. This will be a spur to further drug development in this area.

Tucatinib was not the only new HER2-positive agent examined at ASCO 2020. One group of researchers from China evaluated the role of pyrotinib, a pan-ErbB receptor tyrosine kinase inhibitor in metastatic HER2-positive patients, all of whom had received prior trastuzumab and taxanes and/or anthracyclines, and up to two prior chemotherapy regimens for metastatic disease. Patients received capecitabine with either lapatinib or pyrotinib. The pyrotinib arm outperformed the lapatinib arm, with a significantly increased progression-free survival of 12.5 versus 6.8 months (P < 0.001, hazard ratio of 0.39). Overall survival results were immature but trending in favor of pyrotinib.

While it is always nice to have another new agent, this trial had significant limitations, largely related to differences in the population seen. Patients in the West have generally seen trastuzumab, pertuzumab, and T-DM1 before they reach a receptor tyrosine kinase inhibitor, so the applicability of these results to a HER2-positive patient in my clinic is uncertain. It is also hard to know where to place this agent in the setting of other recently approved (and highly efficacious) agents such as tucatinib and the antibody drug conjugate trastuzumab deruxtecan. We now have a cornucopia of HER2-targeting agents for metastatic disease and ordering all of them in the absence of comparative data is a problem.

There were a number of interesting but non-transformative adjuvant or neoadjuvant HER2 trials. An update on the KAITLIN trial, which had previously demonstrated the superiority of T-DM1 over trastuzumab in the post-neoadjuvant setting residual disease setting, failed to demonstrate any particularly useful biomarkers for T-DM1 benefit, though high HER2 expression in the residual setting predicted worse trastuzumab outcome, as did low PD-L1 expression.

Another trial, TRAIN-2, studied neoadjuvant chemotherapy with or without 3 cycles of anthracyclines. Anthracyclines added nothing to efficacy, worsened quality of life, and were associated with more delays and dose reductions. I believe, and have thought for some time (since the CLEOPATRA trial data became available), that anthracyclines no longer have a place in HER2-positive breast cancer.

Do we need to use chemotherapy at all in the HER2-positive early disease setting? In the provocative PHERGain trial with immature results, Dr. Javier Cortes and his colleagues used FDG-PET scans in a response-adapted strategy to eliminate chemotherapy in patients having an excellent imaging response. The trial hasn't followed patients long enough to judge disease-free and overall outcomes, but it points to a future in which we might appropriately eliminate chemotherapy altogether for some HER2-positive patients, as we have done with many early stage ER-positive patients.

ER-positive disease at the ASCO annual meeting is best characterized as a series of interesting disappointments. The greatest of these didn't occur at the meeting, but in a parallel press release announcing that the PALLAS trial had been declared futile by its data safety monitoring committee. PALLAS was a large, well-conducted adjuvant trial testing the role of the CDK 4/6 inhibitor palbociclib in early-stage disease. Sadly, and strangely, it had no role, despite impressive results in the metastatic setting.

One piece of evidence corroborating the PALLAS results was presented. The FELINE trial (my favorite acronym at this year's meeting) randomly assigned patients to letrozole plus either ribociclib or a placebo with a primary endpoint of PEPI score, a commonly used measure of endocrine response in prior neoadjuvant endocrine therapy trials. There was no difference between the two groups, unless one draws comfort from a p value of 0.96, nor was there any difference with regard to clinical or imaging responses. Of course, the breast need not be a surrogate for micrometastatic disease, but the FELINE results were not catnip for CDK 4/6 inhibitor fans.

These failures (briefly) left the field at a loss. Was PALLAS (and, to a lesser extent, FELINE) a failure of one drug, or of one trial (trial design is important), or a failure for the larger CDK 4/6 inhibitor field? I've tended to think that the CDK 4/6 inhibitors were all essentially the same, based on the similar trial hazard ratios in the front- and second-line settings, so I was concerned that this might be a failure of CDK 4/6 inhibitors rather than of one drug or one trial. Fortunately, the answer came quickly, in another press release announcing that the monarchE trial of adjuvant abemaciclib was positive for its primary endpoint.

We will, of course, need to await the published, peer-reviewed results of these trials to come to any real conclusions. Knowing the magnitude of benefit, as well as the extent of toxicity is crucial, and learning why one trial failed and another succeeded will be of interest, if only to my fellow breast cancer geeks. Nevertheless, there is joy in Mudville tonight.

Dr. Cynthia Ma presented the Alliance ALTERNATE neoadjuvant endocrine trial, which randomized patients to anastrozole alone or to fulvestrant plus anastrozole. In results reminiscent of the (generally forgotten) combination of tamoxifen and anastrozole in the old ATAC trial, the combination was no better than single-agent aromatase inhibitor with regard to the trial's primary endpoint of estrogen sensitive disease rate (ESDR).

And finally, let's take a look at triple-negative breast cancer, where there were a number of interesting results. The KEYNOTE-355 trial randomized frontline metastatic triple-negative breast cancer patients to chemotherapy alone, or to chemotherapy plus the checkpoint inhibitor pembrolizumab, with co-primary endpoints of progression-free and overall survival. Chemotherapy type was at the physician's discretion, and patients were eligible regardless of PD-L1 status. Pembrolizumab improved progression-free survival only in patients with a CPS score greater than or equal to 10 (i.e., in patients with significantly elevated PD-L1 scores), going from 5.6 to 9.7 months. Overall survival data are immature. These results are generally consistent with the IMpassion 130 trial results that led to the approval of atezolizumab for metastatic frontline triple-negative breast cancer.

The other quite interesting triple-negative breast cancer result came from a Chinese cooperative group's SYSUCC-001 trial, which examined maintenance capecitabine therapy. The trial consciously used a metronomic approach to capecitabine, giving 650 mg/m2 twice daily for an entire year following standard adjuvant chemotherapy. With 5 years of follow-up, disease-free survival was 83 percent in the capecitabine arm compared to 73 percent in the control arm, with similar distant disease-free survival improvements. Overall survival results are immature, but trending in favor of the capecitabine arm. These results remind one of the CREATE-X trial results in the post-neoadjuvant residual disease setting. Capecitabine may play a special role in triple-negative breast cancer, and I await this trial's peer-reviewed publication and mature overall survival results with great interest.

Reviewing ASCO highlights is always fraught with hazard. You may miss what's important or offend your friends for failing to discuss their study. Often what is really important is an abstract chosen for a poster presentation where the data was immature at the time of submission, the results were preliminary to a larger definitive trial. In the past, I could always say: "No matter—they'll update us at next year's meeting." I hope that's the case. I miss Chicago, and my friends from around the world, and I so want next June to be something approaching normal. Until then, stay healthy, my friends, and avoid those little COVID beasties.