Overcoming CDK4/6 Inhibitor Resistance in HR-Positive/HER2-Negative Breast Cancer

by Charles Bankhead

From: medpagetoday.com’In the decade since palbociclib (Ibrance) received FDA approval, results from multiple clinical trials have provided a strong evidence base to make cyclin-dependent kinase (CDK)4/6 inhibitors, in combination with endocrine therapy, a first-line standard of care for metastatic hormone receptor (HR)-positive/HER2-negative breast cancer. Research and clinical experience have also shown that resistance to CDK4/6 inhibitorsis inevitable.

The optimal approach to treatment in the post-CDK4/6 inhibitor setting remains undefined, but multiple strategies have emerged, including sequencing agents in the class. Increasingly, molecular testing informs clinical decision-making.

“For the patient who is a candidate for second-line treatment, we know that it’s very important to perform NGS [next-generation sequencing] of tumor plasma to look for actionable alterations and then define the best second line of treatment,” said Mafalda Oliveira, MD, PhD, of Vall d’Hebron University Hospital in Barcelona, during an education session at the San Antonio Breast Cancer Symposium (SABCS).

“If there is no alteration, there are several options [including sequencing]. Then we will look for BRCA1/2, PALB2 mutations, PIK3CA mutations, AKT1 mutations, PTEN alterations, and of course, ESR1 mutations. We may also consider chemotherapy or an ADC [antibody-drug conjugate] if there is no indication for second-line endocrine-based therapy.”

Key Studies of Post-CDK4/6 Inhibition

Oliveira briefly reviewed five studies of CDK4/6 inhibition after progression on initial CDK4/6 inhibitor therapy. Three of the trials showed statistically significant improvement in progression-free survival (PFS) with sequencing.

• MAINTAIN: Almost a twofold increase in PFS with second-line ribociclib (Kisqali) versus placebo, each paired with a different endocrine agent than what was used in the first-line setting (5.3 vs 2.8 months, HR 0.57, P=0.006)
• postMONARCH: Modest but statistically significant improvement in PFS (6.0 vs 5.3 months, HR 0.73, P=0.02) with second-line abemaciclib (Verzenio)
• EMBER-3: More than twofold median PFS improvement with abemaciclib plus the selective estrogen receptor degrader (SERD) imlunestrant (Inluriyo) versus imlunestrant monotherapy (9.1 vs 3.7 months, HR 0.51, 95% CI 0.38-0.68)

The PACE and PALMIRA trials showed no significant improvement in second-line PFS with palbociclib-containing regimens following first-line palbociclib.

A recent meta-analysisof the five trials showed a consistent PFS benefit across subgroups, driven primarily by trials that switched both the endocrine agent and the CDK4/6 inhibitor. The benefits occurred irrespective of PIK3CA or ESR1 mutations, said Oliveira.

A paucity of data have accumulated to help predict response to second-line CDK4/6 inhibition, she continued. One small retrospective study showed that regardless of the cause of first-line treatment failure (toxicity or disease progression), the time to second-line treatment failure was similar whether patients received the same CDK4/6 inhibitor or a different one.

“Patients who had a short time to treatment failure for second-line CDK4/6 plus endocrine treatment had an enrichment in some alterations, like RB1, CDK4 amplification, and TP53 mutations,” said Oliveira. “Perhaps this is telling us that if you perform NGS testing for patients progressing on first-line CDK4/6 inhibitors and find any of these alterations, that might raise a flag that these patients may not respond.”

New Targets, Same Goal

As new targeted agents have emerged, NGS testing has taken on new significance as guidance for second-line therapy. For patients with PIK3CA/AKT1/PTEN mutations or alterations, several potential therapies have FDA approval: everolimus (Afinitor), alpelisib (Piqray), capivasertib (Truqap), and inavolisib (Itovebi)

In the CAPItello-291 trialof capivasertib plus fulvestrant, 73% of patients had already received a CDK4/6 inhibitor. As compared with fulvestrant alone, the combination more than doubled the median PFS, reducing the PFS hazard by 50%.

Of the four drugs reviewed by Oliveira, capivasertib had the lowest incidence of grade 3 or higher adverse events (AEs), but she noted that the most common and/or troublesome AEs differ from one drug to the other.

In a yet-to-be published systematic review and network meta-analysis, Oliveira and colleagues evaluated 10 potential treatment strategies that might be considered after progression on first-line CDK4/6 inhibition. The analysis did not look so much at specific drugs as it did therapeutic strategies, she said. Several “interesting” observations emerged. For example:

• An oral SERD outperformed fulvestrant
• Switching CDK4/6 inhibitors to pair with fulvestrant works better than using the same CDK4/6 inhibitor
• A triplet combination may offer greater benefit than switching CDK4/6 inhibitors to pair with fulvestrant
• For patients with PI3K alterations, an oral SERD plus CDK4/6 inhibitor, or fulvestrant plus PI3K/AKT/mTOR inhibitor appears to work best

“This kind of work, testing different strategies in the absence of randomized data, is valuable, together with real-world evidence that we are generating, to help us understand which is the best strategy for our patients,” said Oliveira.

More Options and Complexity

Options for the post-CDK4/6 inhibitor setting continue to increase. Novel agents targeting the estrogen receptor (ER) include two FDA-approved SERDs (elacestrant [Orserdu]

and imlunestrant) and two others still in clinical trials (giredestrant and camizestrant), noted Erica Mayer, MD, of the Dana-Farber Cancer Institute in Boston, at the SABCS session. Other ER-targeting agents in various stages of development include vepdegestrant, a proteolysis-targeting chimera; palazestrant, a complete estrogen receptor antagonist; and lasofoxifene, a selective estrogen receptor modulator (SERM).

Saying “there is nothing magical about the CDK4/6 inhibitor,” she noted that endocrine sensitivity is the key to effective treatment. Disease stability for a year on prior therapy suggests endocrine sensitivity, which has been helpful in deciding which patients should be considered for oral SERD therapy.

Combination therapy has outperformed single-agent therapy. The recently reported evERA trial was one of the first to compare two different combination therapies in advanced HR-positive/HER2-negative breast cancer. The results showed that giredestrant plus everolimus significantly improved PFS versus endocrine therapy plus everolimus in the overall population and the ESR1-mutant subgroup.

“Although we are talking about the metastatic setting, these agents may be moving into the earlier-stage setting as well,” said Mayer.

Toward that end, the SERENA-6 trialcompared two strategies in patients with ER-positive/HER2-negative advanced breast cancer treated for at least 6 months with an aromatase inhibitor (AI) and a CDK4/6 inhibitor with no evidence of progression. Patients were randomized to continue the existing therapy or switch to camizestrant paired with the existing CDK4/6 inhibitor and placebo AI.

Median PFS improved from 9.2 months with the existing regimen to 16 months with the switch, representing a 56% reduction in the risk for disease progression or death (P<0.00001). The switch also was associated with delayed time to deterioration of patient-reported symptoms and functioning.

At least two phase III trials are evaluating an oral SERD plus CDK4/6 inhibition as first-line therapy for advanced breast cancer, said Mayer.

“A wealth of choices are coming for us, which is wonderful for us and our patients, but also going to create a little more complexity for us in the clinic,” said Mayer. “I would propose that the era of endocrine monotherapy for ER-positive metastatic breast cancer is over. With rare exceptions, I think we should be striving to provide endocrine therapy with targeted partners for our patients, certainly in the post-CDK4/6 setting, and perhaps in all lines of therapy. We have multiple options available after a CDK4/6 inhibitor, but a lot of choices to make.”

What’s Next?

Closing out the SABCS education session, Shom Goel, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Australia, reviewed several categories of emerging therapies that will add more options to the decision-making process to overcome CDK4/6 inhibitor resistance. They include inhibitors that work in the same part of the cell cycle as CDK4/6 inhibitors, such as selective inhibitors of CDK2 and CDK4, as well as inhibitors of CDK7 and KAT6.

“It’s already a very complicated landscape,” said Goel. “It’s very challenging because I think our understanding of the biology of ER-positive breast cancer is better than ever before. It’s growing very quickly, and also happening at record speed is our ability to design molecules that bind to and inhibit these targets. We’re sort of at a point where the biology and the drug discovery are outpacing the trial framework. We cannot test every drug in the right setting, in the right combination.”

“As much as biology is critical and drug discovery is critical, we may also find that we have to be guided simply by thoughtful empiricism and by the toxicity data, as much as the efficacy data,” he added. “Every trial, we have to look at both sides of that coin to work out whether the balance truly does make sense.”