Part XI · Hormone receptor-positive, HER2-negative disease · Chapter 65

CDK4/6 inhibition, combinations and sequencing

What the record settles about adding, continuing, switching and deferring a CDK4/6 inhibitor.

1 · Scope, and why the three agents are not interchangeable

This chapter covers CDK4/6 inhibition in metastatic hormone receptor-positive, HER2-negative disease. It takes the first-line combinations and what each has shown for survival, then the evidence after first progression. It then asks whether to continue the class beyond progression, and whether to give it first at all. It closes on the resistance mechanisms worth testing for and the toxicity differences that decide agent choice in clinic.

The endocrine partner is argued in Endocrine therapy and receptor degraders after progression, which also covers what to do when an ESR1 mutation appears. Conjugates and chemotherapy are in Conjugates and chemotherapy in later lines. Cell cycle biology is in Cell cycle regulation, resistance mechanism detail in CDK4/6 inhibitor resistance, Rb loss, cyclin E, and bypass pathways, and agent pharmacology in Targeted therapy. The clinical framing of the whole branch is in Endocrine resistance, and the presentations the sequence does not fit.

That table is the whole reported record for this position. It is not one question asked twenty-five times. It is six questions, and a row means very little until you know which of the six it belongs to.

Ten trials added an inhibitor to endocrine therapy and compared that against the same endocrine therapy alone. They are PALOMA-1 / TRIO-18, PALOMA-2, PALOMA-3, MONALEESA-2, MONALEESA-3, MONALEESA-7, MONARCH 2, MONARCH 3, DAWNA-1 and DAWNA-2. Three set an inhibitor combination against chemotherapy instead: RIGHT Choice, PEARL and Young-PEARL / KCSG-BR15-10. Six asked what to do once the disease had progressed on the class: MAINTAIN, postMONARCH, PACE, PALMIRA, BioPER and TRINITI-1. Three asked what else belongs in the regimen beside the inhibitor: INAVO120, VIKTORIA-1 and EMBER-3. Two kept the inhibitor running and changed the endocrine partner on a circulating tumour DNA signal, PADA-1 and SERENA-6. One randomised the timing rather than the drug, SONIA.

Palbociclib, ribociclib and abemaciclib are routinely described as a class. They inhibit the same two kinases and they produce broadly similar effects on progression-free survival in the first line. Three things separate them and none is visible in a class label. They differ in what has been shown for survival, which is the subject of the next two sections. They differ in dominant toxicity, which is the subject of the last. They differ in schedule and monitoring burden, which determines what a year on treatment is like.

What the table cannot show is any comparison between the agents. No row in it randomised one inhibitor against another, in any line. No trial in the registry that has yet to report does so either. Every ranking of the three is a contrast across trials that differ in endocrine partner, enrolment year and what patients were allowed afterwards. DAWNA-2 was run in Chinese hospitals alone¹¹, so the fourth member of the class has been tested in one country's practice rather than in many. This block also admits exploratory work, which is why two single-arm studies sit among the randomised ones. The sections below take randomised slices and say when they are doing otherwise.

2 · First-line combinations and their overall survival results

Seven of the twelve rows below added an inhibitor to the endocrine therapy the patient would have received anyway. The other five are first-line trials that ask something else, and they are in the table because the filter is a position in the disease rather than a question.

Across those seven the progression result is the same finding repeated. Adding the inhibitor lengthened time to progression against the identical endocrine partner given alone. That held for three agents in wide use and for a fourth. It held in postmenopausal and in premenopausal disease, and whether the partner was an aromatase inhibitor or fulvestrant. The hazard ratios cluster tightly enough to read as one property of the class. That is the only class-level claim the first line supports.

The survival column does not behave like the progression column, and the differences in it are mostly differences of design. Ribociclib has three survival results pointing one way. MONALEESA-2 was positive with letrozole in postmenopausal disease²⁶, after an updated progression analysis²⁷. MONALEESA-7 was positive in pre- and perimenopausal women, all of whom received ovarian suppression²⁸, after a progression-free survival result reported first¹⁹. MONALEESA-3 was positive with fulvestrant²⁹. The third of those is weaker than it looks as evidence about first-line treatment. It enrolled patients who were treatment naive or who had already had one endocrine line¹⁸. Its first-line median survival comes from an exploratory subgroup analysis rather than from the whole trial, so it is not the same kind of result as the other two³⁰. Palbociclib and abemaciclib each have one phase III first-line survival result and neither reached significance^31,32. Dalpiciclib has none at all, because DAWNA-2 reported a preplanned interim progression analysis and no survival data¹¹. PALOMA-1 / TRIO-18 is the randomised phase II that preceded PALOMA-2, and the larger trial supersedes it²⁵. It was nonetheless the trial on which the United States regulator granted palbociclib accelerated approval, in February 2015³³. The approval rested on a progression-free survival hazard ratio of 0.488 and was contingent on confirmation in PALOMA-2.

What can be said structurally is narrower than a ranking and more useful. The ribociclib result is replicated across three separate populations, one of which mixed first-line and second-line patients. Replication across populations is a different kind of evidence from a single analysis, whichever way that analysis fell. MONARCH 3 is the awkward row, because its point estimate favours abemaciclib and does not clear its boundary³². Not significant there is a statement about the alpha remaining after the interim looks, rather than about the direction of the curve.

One feature of the palbociclib result is a measurement problem rather than a biological one, and the authors say so. Survival status was unknown at analysis for a substantial minority of patients, and for more of them in the placebo arm than in the palbociclib arm³¹. Loss to follow-up in that direction removes control-arm deaths from view. A negative result with a censoring imbalance is not the same object as a negative result without one.

Three explanations compete for the pattern and none has been established. The drugs may differ pharmacologically, since they are not equipotent against the two kinases and are not given on the same schedule. The trials may differ in conduct and follow-up, which the palbociclib censoring imbalance demonstrates directly. Or the survival differences may be noise, given how closely the progression results agree. No first-line trial in this group carried overall survival as its primary endpoint. Every survival result here is a secondary endpoint from a trial powered for progression.

The decision to start an inhibitor in the first line does not in fact rest on any of that. It rests on the seven progression results, which agree. Where the choice is not endocrine therapy alone but chemotherapy, the load-bearing trial is RIGHT Choice, because it is the only first-line trial here whose control arm is what such a clinic would otherwise do. It randomised premenopausal women with clinically aggressive disease, most of whom had symptomatic visceral metastases. The comparison was ribociclib with endocrine therapy against investigator's choice of combination chemotherapy. The endocrine arm lengthened progression-free survival against that comparator⁸. Overall response rates were close in the two arms. Median time to response was longer with the endocrine combination, and that is the cost a clinic weighs when the disease is moving. A smaller phase IV trial, PADMA, used single-agent chemotherapy as the comparator in mostly postmenopausal patients and also favoured the endocrine combination³⁴. It is set out in Rapid progression and visceral crisis.

The remaining rows answer other questions and are argued elsewhere. PADA-1 and SERENA-6 both continued the inhibitor in both arms and randomised only the endocrine partner, triggered by an ESR1 mutation rising in circulating tumour DNA before radiological progression^13,35. They are evidence about the receptor rather than about the kinase, and they belong to Endocrine therapy and receptor degraders after progression. Their result also belongs to a sampling scheme rather than to a drug. SERENA-6 tested every two to three months, and only a positive test opened the door to randomisation¹. A clinic that does not run that surveillance cannot reproduce the population the result describes. INAVO120 enrolled the most endocrine-resistant first-line population in the table, PIK3CA-mutated disease relapsing during adjuvant endocrine therapy or within 12 months of completing it, and both of its arms contained palbociclib⁶. It is a trial of a third drug, not of the inhibitor. SONIA is the next section.

Three things the table cannot carry. A blank in the survival column means immature rather than negative, and DAWNA-2, PADA-1 and SERENA-6 are all in that state. What the control arms received after progression was not controlled and differed between protocols, and SONIA alone guaranteed its control arm an inhibitor by design. And no trial here enrolled a patient who had already had a CDK4/6 inhibitor in the adjuvant setting. That is a growing share of the clinic and the one first-line population with no randomised evidence at all.

3 · Second-line and later combinations

Single-agent activity came first. In MONARCH 1, continuous abemaciclib alone was active in heavily pretreated, refractory disease, with infrequent discontinuation for adverse events³⁶.

The trials after first progression divide into two eras, and conflating them is the commonest misreading of this table. The dividing line is not the year. It is whether the patients had already had a CDK4/6 inhibitor.

Four rows belong to the first era, and a fifth is there for a narrower reason. MONALEESA-7 was a first-line endocrine trial in premenopausal disease, and it appears only because it admitted patients after one line of chemotherapy for advanced disease. MONARCH 2, PALOMA-3 and DAWNA-1 added an inhibitor to fulvestrant in patients progressing on endocrine therapy, and the second-line stratum of MONALEESA-3 did the same^20,24,14,18. All of them lengthened progression-free survival. Their survival results differ, and the difference tracks the population rather than the drug. MONARCH 2 required progression on endocrine therapy within defined windows and reported a survival benefit³⁷. PALOMA-3 admitted any menopausal status and patients with primary endocrine resistance. It missed significance on survival overall. Its benefit sat in the patients with documented sensitivity to prior endocrine therapy³⁸. That subgroup finding is consistent with the resistance definitions in Defining endocrine sensitivity and resistance in clinical language and is one of the few places where the clinical timing convention predicts something. DAWNA-1 has reported no survival data at all¹⁴.

This population has almost disappeared. A patient reaching second line today has nearly always had an inhibitor already. These four trials describe a decision that is now rare, and quoting them to justify a second inhibitor after first-line inhibitor failure is quoting the wrong evidence. MONALEESA-7 also appears in the table above, but only because it admitted one chemotherapy line for advanced disease. Its patients had had no endocrine therapy for advanced disease, so it belongs with the first-line trials^19,28.

Two rows ask a different question again and they appear to disagree. PEARL and Young-PEARL / KCSG-BR15-10 both compared a palbociclib-containing endocrine regimen against capecitabine, and only the smaller of the two met its endpoint^16,17. The disagreement is population, not drug. PEARL enrolled postmenopausal women resistant to an aromatase inhibitor and read its co-primary endpoints in a fulvestrant cohort and in ESR1 wild-type patients. Young-PEARL / KCSG-BR15-10 enrolled premenopausal women progressing on tamoxifen, and gave exemestane with ovarian suppression. Its patients therefore came to the trial off tamoxifen rather than off an aromatase inhibitor. Neither trial found a survival difference against capecitabine^39,40. What separates the two options is therefore tolerability rather than outcome. PEARL is the trial that measured it. Time to deterioration of global health status favoured palbociclib, at an adjusted hazard ratio of 0.67 against capecitabine¹⁶.

Four more rows are the post-progression trials, MAINTAIN, postMONARCH, PACE and PALMIRA. They are the modern second line and they are argued in the next section. PACE also admitted patients who had received up to two endocrine lines and one chemotherapy line for advanced disease.

The last two rows put a third drug on the backbone. EMBER-3 carried a third arm of imlunestrant with abemaciclib. Among the patients randomised concurrently to those two arms, the combination lengthened progression-free survival against imlunestrant alone³. Its population had recurred or progressed on an aromatase inhibitor, given with or without a CDK4/6 inhibitor. Two readings of that arm are possible and the trial does not separate them. Adding a CDK4/6 inhibitor to a receptor degrader may recover cell cycle control that endocrine therapy alone cannot deliver. Or two drugs may simply beat one. That arm, and what it does and does not establish, is set out in Oral selective estrogen receptor degraders and their biomarker-defined benefit. VIKTORIA-1 randomised gedatolisib with fulvestrant, with or without palbociclib, against fulvestrant alone, in PIK3CA wild-type disease and with blinded central review². The effect sizes are the largest in the table and the control arm is the reason to read them carefully. Fulvestrant alone ran shorter there than in any other trial in this table. A comparator that performs unusually badly inflates every hazard ratio measured against it.

What this table cannot show is the choice a clinic actually makes after first-line inhibitor failure. Nobody has randomised a post-progression endocrine combination against an antibody-drug conjugate Conjugates and chemotherapy in later lines. Nobody has randomised the decision to stay endocrine against the decision to move to chemotherapy in patients who have already had an inhibitor. The capecitabine comparisons above predate that population. VIKTORIA-1 has short follow-up and no survival data, so it says nothing yet about durability.

4 · Continuation beyond progression and the switch question

Four randomised trials have asked what to do with the inhibitor at progression, and two single-arm studies asked it without a control. They are usually summarised as showing that continuing the class helps. Read together they show something more specific and more useful.

Both trials that introduced a different inhibitor were positive. MAINTAIN switched patients to ribociclib¹². postMONARCH switched to abemaciclib⁵. Both trials that kept palbociclib were not. PACE continued it⁷, and PALMIRA restarted it after a break⁴. The two single-arm studies met their own thresholds. BioPER rechallenged with palbociclib and a changed endocrine partner¹⁰, and TRINITI-1 gave ribociclib with everolimus and exemestane together¹⁵. Neither threshold was set against a comparator, and TRINITI-1 changed three drugs at once, so what it shows cannot be assigned to the kinase.

The divergence is in the designs and it runs deeper than switch against continue. The two negative trials both continued palbociclib. The two positive trials both introduced an inhibitor that most of their patients had not had. Whether what matters is the act of switching or the identity of the new agent is not separated by any of them. The endocrine half moved too, and it moved differently in each. MAINTAIN switched the endocrine partner in both arms, which isolates the inhibitor at the cost of making the answer one about a switched partner. postMONARCH held fulvestrant in both arms after aromatase inhibitor failure. PACE switched both arms to fulvestrant and varied only the palbociclib. Its third arm added avelumab and sat outside that primary comparison.

The decision rests on postMONARCH. It is the only phase III among them, its control arm is the fulvestrant a clinic would otherwise give, and nothing but the inhibitor differs between its arms. Its primary endpoint was investigator-assessed, and blinded central review of the same comparison returned a considerably larger effect, a hazard ratio of 0.55 against 0.73⁵. The trial was double blind, so that gap is reader-to-reader variability in measuring progression rather than bias from knowing the allocation. It is a reminder that the size of a small effect in this setting is partly a property of who reads the scans.

Three things none of these trials can show. No trial randomised continuation against switching, so that contrast is across trials with different endocrine designs. In each randomised trial most patients had progressed on palbociclib. What is being tested is therefore mainly a second inhibitor after palbociclib rather than after ribociclib or abemaciclib. None has reported overall survival. One more caution sits in the control arms. Endocrine monotherapy begun at progression performed differently across these trials. The spread between their control arms is of the same order as the gains being argued over.

The mechanistic reason for scepticism is set out in CDK4/6 inhibition and the evolution of cell cycle escape. A tumour that progressed on a CDK4/6 inhibitor is enriched for cells that no longer need CDK4 and CDK6. Blocking them again is coherent only if the escape was partial, or if the escape was endocrine rather than cell cycle. That reasoning has been acted on, by bringing mechanisms from outside both classes into the same resistant population.

No randomised comparison in that table beat its own control, and the three fail in different ways. VERONICA is the only clean test of its own hypothesis, because it randomised the addition of the BCL2 inhibitor to fulvestrant, and the addition gained nothing⁴³. TBCRC 041 randomised only whether fulvestrant was added to an Aurora A kinase inhibitor, so both arms received the experimental drug. Adding fulvestrant did nothing, and what activity the trial saw belongs to the kinase inhibitor given alone, which has no control anywhere in the trial⁴². Study G200802 randomised one dose of an androgen receptor agonist against another, with no standard-therapy arm at all⁴¹. Its clinical benefit rate describes a cohort and ranks nothing.

None of the three selected patients on the marker its own hypothesis names, which is why each is negative about a combination and a schedule rather than about a mechanism. VERONICA looked for a BCL2-defined subgroup only after the fact, in small exploratory analyses⁴³. The same failure mode has been repeated at phase III scale in E2112. It added a histone deacetylase inhibitor to exemestane without selecting for anything, and moved neither progression-free survival nor overall survival. Its patients were mostly CDK4/6 naive, so it tested the reversal of aromatase inhibitor resistance rather than resistance to the combination⁴⁴.

The androgen receptor rows raise a measurement problem rather than a biological one. Study G200802 read its primary endpoint only in patients whose androgen receptor positivity was confirmed centrally after randomisation, and a quarter of those randomised fall outside that population⁴¹. Positivity is a nuclear staining cut-off fixed by protocol rather than a biological boundary. The antagonist studies in receptor-negative disease, TBCRC 011 and TBCRC 032, state the threshold they used^45,46. The agonist record does not state its own, so the two conventions cannot be checked against each other. The stain does not settle the question in any case. TBCRC 032 concluded that receptor protein expression alone did not identify which tumours depended on the receptor, and an exploratory analysis separated responders from non-responders better by transcriptional subtype⁴⁶. Nothing anywhere compares agonism with antagonism in the same tumour, and the two pharmacologies were tested in populations defined by opposite oestrogen receptor status.

None of this makes switching the inhibitor a good bet on its own merits. It does mean that outside the pathway inhibitors and the conjugates there is currently nothing better to switch to.

5 · First-line use against deferred use

SONIA is the most important trial in this chapter for practice and the most frequently misdescribed. It deserves a careful reading of its design before any reading of its result.

The trial randomised patients with no prior therapy for advanced disease to one of two strategies rather than to two drugs⁹. In one, the inhibitor was given first line with an aromatase inhibitor, and second line was fulvestrant alone. In the other, first line was an aromatase inhibitor alone, and the inhibitor was added to fulvestrant at second line. Both arms received the inhibitor. Only the timing differed.

The primary endpoint was second progression-free survival, measured from randomisation to the second objective progression or death. That endpoint is not a technicality and it is the reason the trial can answer the question at all. Progression-free survival on first-line therapy would necessarily favour the arm given two drugs first. Only an endpoint running across both lines can compare strategies rather than treatments.

Neither that endpoint nor overall survival separated the two strategies^9,47. Median inhibitor exposure was 24.6 months with early use against 8.1 months with deferred use, and the early arm accumulated more grade 3 or worse adverse events⁹. Much more drug, a much longer window of toxicity, and no measurable difference in either endpoint. Every patient pays that price. Only the subgroup that benefits collects.

Two later analyses restrain the simple reading and both point the same way. A post hoc subgroup analysis found a survival advantage for first-line use in premenopausal patients and none in postmenopausal patients, with a significant test for interaction⁴⁷. A circulating tumour DNA analysis then divided patients by baseline genome-wide aneuploidy score. Those with a high score gained on the across-line endpoint from first-line use, and those with a low score did not⁴⁸. A trial that is negative overall is not negative in everyone.

One further limit is easy to miss. The deferred arm is underwritten by second-line trials run in patients who had never had an inhibitor, which is exactly the population that no longer exists Second-line and later combinations. A patient who defers today is being offered a second line whose evidence base was generated in someone else.

The economic consequence is the part most likely to change practice at a system level. A strategy that delivers the same outcome with a fraction of the drug exposure is a different proposition for a health service than for an individual patient. That distinction is developed in Access, affordability, and financial toxicity.

6 · Resistance mechanisms that change the next choice

Most progression on a CDK4/6 inhibitor is not explained by any measurable mechanism. That sentence should come first, because the literature on this subject is much larger than the fraction of patients it accounts for.

Five mechanisms are documented well enough to discuss. They divide into two groups with opposite implications.

Cell cycle escape removes the drug's target. RB1 loss is the clearest example and it is uncommon, appearing in the palbociclib arm alone in the paired analysis described in CDK4/6 inhibition and the evolution of cell cycle escape⁴⁹. High cyclin E1 expression predicts poor benefit from palbociclib and describes a cell cycle driven through CDK2 rather than CDK4 and CDK6⁵⁰. FAT1 loss raises CDK6 through the Hippo pathway⁵¹. In all three the kinase the drug blocks has become dispensable, so more of the same class is a poor bet.

Endocrine escape leaves the target intact. ESR1 mutation confers ligand independence without touching the cell cycle machinery Endocrine therapy and the emergence of ESR1 alterations. PIK3CA, AKT1 and PTEN alterations activate a parallel growth pathway PI3K, AKT, mTOR, and related networks. In both the inhibitor may still be doing useful work. The alteration then names a drug for the other half of the regimen.

The measurement caveat is the reason none of this is routine. RB1 loss can be found in circulating tumour DNA or by immunohistochemistry. Neither has an established threshold for action. Cyclin E1 was measured as messenger RNA in a trial analysis, not by any assay in clinical use⁵⁰. FAT1 is not on most commercial panels. Only ESR1 and the PI3K pathway alterations are both detectable and actionable today.

7 · Toxicity differences that drive agent selection

Toxicity is where the three agents genuinely diverge. In a patient who will take the drug for years it is often the deciding variable.

Palbociclib produces neutropenia and comparatively little else. Grade 3 or 4 neutropenia occurred in 66.4% of patients in PALOMA-2²³. Febrile neutropenia was rare. The mismatch between those two statements is the point. The neutropenia is a reversible cytostatic effect on the marrow rather than the cytotoxic depletion seen with chemotherapy, so it produces alarming counts and few infections.

Ribociclib produces similar neutropenia and adds two monitoring requirements the others do not have. It prolongs the QT interval, so electrocardiograms are needed at baseline and again in the first weeks of treatment. It causes transaminase elevation, so liver function requires scheduled checks. Both are manageable and both need a system rather than an intention.

Abemaciclib is given continuously and its dominant toxicity is diarrhoea. In MONARCH 3 it affected 81.3% of patients at any grade²¹. Neutropenia is less prominent. Serum creatinine rises in many patients through inhibition of renal transporters, which is not a change in glomerular filtration and does not by itself require dose reduction.

8 · Unresolved questions and what reads out next

Not one of those five trials compares inhibitors. They ask what should be given alongside one, and they fall into three groups.

Three replace the endocrine half of the first-line doublet and hold the inhibitor constant. SERENA-4 and persevERA test an oral receptor degrader against an aromatase inhibitor, and VERITAC-3 tests a degrader built as a targeted protein degradation molecule. All three keep palbociclib in both arms. That makes them the cleanest test yet of whether the endocrine partner, rather than the kinase, is what limits how long the first-line combination holds.

CAPItello-292 adds AKT inhibition to a CDK4/6 inhibitor and fulvestrant, in a biomarker-unselected population spanning first and second line. It will say whether the pathway should be blocked in everybody or only in the patients an alteration names Endocrine therapy and receptor degraders after progression.

ABIGAIL asks the tempo question the first-line trials avoided. It compares immediate abemaciclib with a course of paclitaxel given first, in aggressive disease, which is the same clinical situation RIGHT Choice addressed from the other direction. It is a phase II whose registry entry requires at least one feature of aggressive disease and no prior systemic therapy for advanced disease.

Three questions this chapter raises have no trial attached, and they are the ones a reader will keep meeting in clinic.

No trial compares the three inhibitors head to head, in any line. The survival differences described above will therefore never be resolved by direct comparison. Any future attempt would have to be very large to detect a difference of the size at issue.

No trial randomises continuation of the same inhibitor against a switch to a different one. The inference that switching is what works rests on a contrast across four trials with different endocrine designs, in patients who had almost all received palbociclib.

No trial has tested deferred first-line use in the populations where SONIA suggested an exception. A confirmatory trial in premenopausal patients, or in patients selected by baseline aneuploidy, would convert two subgroup findings into a rule. Until one exists, the safest reading is that SONIA licenses deferral in the average postmenopausal patient and not in the patient in front of you who resembles one of its exceptions.

References

All 51 references

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