By George W. Sledge, Jr., MD
The 2022 American Society of Clinical Oncology Annual Meeting is behind us, leaving us with presents large and small in the breast cancer field. It was, of course, the first time we had met in person since 2019, and I sensed real enthusiasm (and some mild trepidation) about this first post-pandemic get-together with 30,000 of my closest friends (with another 11,000 or so sharing the proceedings online).
The clear “Best in Show" for breast cancer, and perhaps for the field, occurred in the plenary session where Shanu Modi, MD, presented the results of the DESTINY-Breast04 trial of trastuzumab deruxtecan in HER2-low metastatic breast cancer.
By way of background, we have known for 3 decades that HER2 protein expression represents a continuum rather than a sharp yes/no in breast cancer. However, early studies with trastuzumab suggested that only patients with high (3+ by immunohistochemistry) HER2 expression in their cancers, or those with FISH-positive tumors, would respond to HER2-targeted therapy.
While this dichotomy between what we call “HER2-positive" and “HER2-negative" was rational in the naked monoclonal antibody scenario, more recent technologic advances, culminating in this year's ASCO presentation, have forced us to reconsider what we mean by “HER2-positive."
Following prior Phase II data suggesting that many breast cancers with lower levels of HER2 expression (1+ or 2+ by IHC, regardless of estrogen receptor status) might well respond to HER2-targeting therapy with the relatively novel antibody-drug conjugate (ADC) trastuzumab deruxtecan. This agent, of course, is well-known to physicians who treat breast cancer, given its approval for HER2-positive patients in more advanced metastatic settings. The drug has previously shown superiority to the other FDA-approved ADC, trastuzumab emtansine in a Phase III trial (DESTINY-Breast03), and as such has become a go-to drug in the post-trastuzumab/pertuzumab setting.
DESTINY-Breast04 randomly assigned patients with low (1+ or 2+) HER2 expression who had received prior endocrine therapy (if steroid receptor-positive) and 1-2 lines of chemotherapy to receive either a chemotherapy of physician's choice (chosen from a menu of options) or trastuzumab deruxtecan. The results were impressive, with improvements in both progression-free and overall survival; the latter in particular impressed with a median 6.6-month improvement in a field where post-endocrine therapy advances have been pedestrian at best.
Trastuzumab deruxtecan, one suspects, will rapidly become a new standard of care (a phrase I always hesitate to use, but warranted here) in the HER2-low population, though important questions remain regarding its use. In particular, the number of patients with so-called triple-negative breast cancer was relatively small, and while there was no obvious difference between the ER-positive and triple-negative outcomes, more data would certainly be helpful. And, given the emergence of another ADC, sacituzumab govitecan, in the triple-negative space, we will need greater nuance regarding best treatment options in triple-negative-no-longer subgroups. Undoubtedly, we will be subjected to marketing campaigns saying “my ADC is better than your ADC" in the absence of head-to-head comparisons. Given the somewhat scary interstitial lung disease seen with trastuzumab deruxtecan, physicians will need improved management skills with these promising yet toxic agents. What we even call “HER2-low" will require some thought and care; the discussion accompanying the presentation shared data suggesting that pathologists are not particularly agreeable from a concordance standpoint. We can hope that a future ASCO plenary session will deliver answers regarding the adjuvant use of the agent. Time will tell.
Two other presentations examined other antibody-drug conjugates. Hope Rugo, MD FASCO, discussed the TROPICS-02 trial that essentially attempted to recapitulate DESTINY-Breast04 with the TROP-2-targeting ADC sacituzumab govitecan in ER-positive metastatic disease. Median progression-free survival (PFS) was improved by only 6 weeks and overall survival results were immature, so for the moment sacituzumab remains in the triple-negative domain.
Ian Krop, MD, PhD, presented early data with patritumab deruxtecan, a HER3-targeted ADC, in relatively heavily pretreated HER3-positive breast cancers, with promising response rates seen in ER-positive, triple-negative, and HER2-positive patients, though as always with ADCs, interstitial pneumonitis is an issue. Worth keeping an eye on, though too early to claim victory.
Though DESTINY-Breast04 stole the show, several other presentations provided important, or at least interesting, insights into the state of the field.
We have known for many years that the PI3K/AKT/mTOR pathway represents an important alternate signaling pathway in estrogen receptor-positive breast cancer, and a principal means by which other receptors cross-talk with the estrogen receptor, promoting resistance to endocrine therapies. This in turn led to the development of several agents targeting this pathway. Two of these (everolimus for mTOR and alpelisib for PI3K inhibition) are already FDA-approved agents for metastatic breast cancer, and AKT targeting (with capivasertib) is far down the development path.
This year saw an important update on capivasertib. Previously, this agent had been shown to improve progression-free survival in the randomized Phase II FAKTION trial; this year's update looked at the value of biomarker analysis in this trial and provided a peek at the survival effects of this agent.
In brief, FAKTION showed improvements in both progression-free and overall survival, both in the 6-month range. These are results from a randomized Phase II trial and, as such, are underpowered, though both suggestive and promising. We'll need to await the results of the Phase III trial with this agent. Of interest, and of real potential importance, capivasertib appeared to exert its greatest effects in the trial subpopulation with pathway alterations (as measured by next-generation sequencing) in PIK3CA, AKT, and PTEN. We need to be careful regarding subset analyses of randomized Phase II trials, but these results are consistent with what we think we know about how this drug should work, and we will again await the Phase III trial biomarker results with great interest.
Staying in the confines of estrogen receptor-positive breast cancer, we also saw an interesting presentation by Kevin Kalinsky, MD, and colleagues touching on the vexing question of management of patients whose cancers have progressed on frontline CDK 4/6 inhibitor therapy. This investigator-initiated, randomized Phase II trial allocated patients to either fulvestrant alone or to ribociclib and fulvestrant. This MAINTAIN trial demonstrated statistically significant improvements in progression-free survival and clinical benefit rate favoring the combination of fulvestrant and ribociclib.
This was a well-conducted and interesting trial that left me confused as to what to do in clinic. Randomized Phase II trials rarely offer definitive results; they are, in essence, parallel Phase II trials that suffer from (over)comparison. In addition, it is uncertain what question this trial actually asked. Most patients had received initial CDK 4/6 inhibition with palbociclib. Does a positive result imply that we should continue CDK 4/6 inhibition when we change from an aromatase inhibitor to fulvestrant, or does it tell us that ribociclib is a better (i.e., less susceptible to development or resistance) CDK 4/6 inhibitor than palbociclib? And though the trial is positive regarding its PFS primary endpoint, overall survival results are immature, and we know from long experience that a modest PFS increase is not a particularly robust surrogate for overall survival.
The MAINTAIN trial did include an interesting biomarker analysis that may prove important. Crossover to ribociclib appeared to be particularly useful in patients with wild-type ESR1; in contrast, mutations in ESR1 (the estrogen receptor gene) largely abrogated benefit of crossover. Biomarker analyses in randomized Phase II trials, where one deals with ever-smaller subsets and therefore ever-more-dangerous statistical analyses, are inherently suspicious. But, if this one pans out in larger datasets, this could make the MAINTAIN approach an interesting one for an important biological subset.
Finally, with regard to CDK 4/6 inhibitors, we saw the final overall survival analysis of PALOMA-2, presented by Richard Finn, MD. PALOMA-2 was the first randomized, frontline, metastatic trial of an aromatase inhibitor with or without a CDK 4/6 inhibitor, utilizing, respectively, letrozole and palbociclib. The median overall survivals for letrozole alone and for the combination were 51.2 and 54 months, a result that did not reach statistical significance. The presenter, in a feat of death-defying statistical acrobatics, attempted to convince the audience that this was, in fact, a positive trial. I was unconvinced. The basic issue was that the trial was missing a third of patient survival data, which is usually one of the easier datapoints to assess.
A question raised by the Kalinsky and Finn presentations, as well as by prior palbociclib randomized trials in the adjuvant and metastatic settings, is whether it is simply the weakest of the three CDK 4/6 inhibitors. I consider this still an open question; cross-trial comparisons are always fraught with difficulty, and palbociclib trials tended to enroll the toughest patients from the standpoint of a prior endocrine resistance. That being said, I really wish that the drug had a single unalloyed success in the adjuvant or metastatic with regard to either disease-free survival (in the adjuvant setting) or overall survival (in the metastatic setting).
The early disease session held less interest for me this year, as there were no great adjuvant breakthroughs to be seen, though several interesting biomarker analyses. To me, the most interesting early disease trial was the LUMINA trial with Tim Whelan, MD, which tested our ability to eliminate post-lumpectomy radiation therapy in patients with smaller (T1a and b) Luminal A breast cancers.
To make a long story short, this prospective registry trial suggests that for patients aged 55 and older with T1N0 Grade 1 or 2 invasive ductal Luminal A cancers (defined pathologically as: ER ≥1%, PR>20%, HER2-negative, and Ki67 ≤13.25%) and negative margins of resection receiving endocrine therapy, omitting radiation therapy is a reasonable option, with a 5-year rate of local recurrence of 2.3 percent. While these results are compelling, median follow-up is still relatively short. More importantly, the devil is in the details here, with a requirement for careful pathology a necessity if one is to follow this approach.
How do we put all this together? Looking from the 20,000-foot view, Destiny-Breast04's superb trastuzumab deruxtecan's impressive overall survival results in the HER2-low metastatic setting was the clear winner in 2022, and the sole truly practice-changing result. It was a win, not just for a specific drug, but for the concept of applying antibody-drug conjugate therapy to a broader patient population than what we normally think of as the biomarker-selected population. I suspect it will cause several companies to revisit their drug development strategies (sometimes for better, sometimes for worse). Numerous companies are developing such agents, and we'll see many of them at future ASCO Annual Meetings.
On a personal note, it was good to be back in Chicago and to see old friends in person. Indeed, there were people who I had interacted regularly with via Zoom meeting over the past 2 years who I only saw for the first time in the flesh in Chicago. That it was a super-spreader event for COVID-19 I do not doubt; several colleagues and friends came down with the virus on their return. But that did not diminish my pleasure in sitting in the audience, and I look forward to sharing future years with all of you, even if I continue wearing a KN95 mask.