Part VIII · Therapeutic foundations · Chapter 46

Targeted therapy

What each class actually depends on, and what that predicts when it fails.

1 · HER2-directed antibodies

The receptor biology is in HER family signaling and is not restated. What belongs here is that an antibody against HER2 has three mechanisms and a kinase inhibitor has one of them. It blocks signalling, it drives receptor internalisation and degradation, and it engages immune effector cells through its constant region.

The third mechanism has human evidence. Fc gamma receptor polymorphisms were associated with clinical outcome on trastuzumab-based therapy, which is difficult to explain if effector function contributes nothing1. It also explains why loss of the antibody epitope and loss of pathway dependence are separate resistance mechanisms HER2-directed therapy resistance across antibodies and kinase inhibitors.

Adjuvant trastuzumab remains the largest single effect in this chapter. In the joint analysis of two adjuvant trials, 133 events occurred in the trastuzumab group against 261 in the control group. The hazard ratio for recurrence, second primary cancer or death was 0.48. The absolute difference in disease-free survival at three years was 12 percentage points, and the risk of death fell by 33%. Three-year cumulative incidence of class III or IV congestive heart failure or cardiac death was 4.1% and 2.9% in the two contributing trials2.

Pertuzumab blocks the dimerisation interface rather than the trastuzumab epitope, and the structural basis is separate3. In first-line metastatic HER2-positive disease, adding pertuzumab to trastuzumab and docetaxel reduced the hazard of death at the confirmatory overall survival analysis of CLEOPATRA, after a median follow-up of 30 months. The hazard ratio was 0.66, with a 95% confidence interval of 0.52 to 0.844. At the final prespecified analysis in 2015, median overall survival was 56.5 months against 40.8 months, with a hazard ratio of 0.68 and a 95% confidence interval of 0.56 to 0.845. At the final 8-year end-of-study analysis the medians were 57.1 months against 40.8 months, with a hazard ratio of 0.696. That is the current figure, and it is the one used in First-line dual blockade with a taxane. Neither of the later two analyses was adjusted for crossover, so both are conservative rather than optimistic.

Eligibility for all of this is defined by an assay, and the assay has a heterogeneity problem HER2 heterogeneity and an analytic validity framework Receptor assessment and the measurement problem.

2 · HER2 and pan-HER tyrosine kinase inhibitors

A small molecule reaches the kinase domain rather than the extracellular epitope. Three consequences follow and they are the whole case for the class.

A truncated receptor lacking the antibody binding site remains a target in principle7. A mutant receptor without amplification is addressable, with sensitivity that depends on which allele is present8,9. And a small molecule crosses into the central nervous system in a way an antibody largely does not.

That third point is where the class earns its place. Tucatinib was added to trastuzumab and capecitabine in heavily pretreated HER2-positive metastatic disease. The hazard ratio for progression or death was 0.54, with a 95% confidence interval of 0.42 to 0.71, and median progression-free survival was 7.8 against 5.6 months. The hazard ratio for death was 0.66, with an interval of 0.50 to 0.88. Among patients with brain metastases, progression-free survival at one year was 24.9% against 0%10. A rate of zero in the control arm is the reason this result changed practice.

Selectivity is the design variable that decides tolerability. Neratinib inhibits HER1, HER2 and HER4 irreversibly. Given for twelve months after chemotherapy and trastuzumab, it improved two-year invasive disease-free survival. There were 70 events in 1420 patients against 109 in 1420, giving a stratified hazard ratio of 0.67 with a 95% confidence interval of 0.50 to 0.91. Grade 3 diarrhoea occurred in 561 of 1420 patients, which is 40%11. EGFR inhibition bought the diarrhoea. It did not buy the HER2 activity.

Antibodies and kinase inhibitors also fail differently, which is why progression on one is weak evidence about the other12. Sequencing after progression is developed in Second-line conjugate therapy.

3 · CDK4/6 inhibitors and next-generation cell cycle agents

The cell cycle mechanism is in Cell cycle regulation. The point that belongs here is that this class was predicted to work in luminal disease before it was tested. Oestrogen receptor positive lines were preferentially sensitive in vitro, and receptor-negative lines were not13. The prediction held.

Two first-line trials give the size of the effect. Palbociclib with letrozole gave median progression-free survival of 24.8 months against 14.5 months with letrozole alone, with a hazard ratio of 0.58 and a 95% confidence interval of 0.46 to 0.7214. Ribociclib with letrozole gave a hazard ratio of 0.56, with an interval of 0.43 to 0.72, and progression-free survival at 18 months of 63.0% against 42.2%15.

The toxicity is worth reading carefully because it is routinely misread. Grade 3 or 4 neutropenia occurred in 66.4% of patients on palbociclib against 1.4% on placebo, while febrile neutropenia occurred in 1.8% against none14. Grade 3 or 4 neutropenia occurred in 59.3% on ribociclib against 0.9% on placebo15. Neutropenia at that rate with febrile neutropenia under 2% is a different clinical object from chemotherapy neutropenia. The mechanism is reversible arrest of a dividing marrow compartment rather than killing of progenitors.

In early disease the class produces a consistent effect in two differently selected populations. Abemaciclib with endocrine therapy in node-positive high-risk disease gave a hazard ratio for invasive disease-free survival of 0.75, with a 95% confidence interval of 0.60 to 0.93. Two-year rates were 92.2% against 88.7%16. Ribociclib with a non-steroidal aromatase inhibitor in stage II or III disease gave a hazard ratio of 0.75, with an interval of 0.62 to 0.91. Three-year rates at that prespecified interim analysis were 90.4% against 87.1%17. The final preplanned analysis gave 0.749 and three-year rates of 90.7% against 87.6%, and the later data cuts are set out in NATALEE, a broader population at a lower dose18. The same hazard ratio in two different eligible populations is the useful observation, because what differs is the selection rule rather than the drug.

Next-generation agents follow from the escape biology rather than from screening. Cyclin E1 expression marks a cycle that does not depend on the blocked kinase19, which is the argument for targeting further down. Resistance is developed in CDK4/6 inhibitor resistance, Rb loss, cyclin E, and bypass pathways.

4 · PI3K, AKT, and mTOR inhibitors

Pathway architecture is in PI3K, AKT, mTOR, and related networks. What this section adds is that every agent in the class is fighting the feedback its own mechanism creates. Inhibiting mTOR raises insulin receptor substrate 1 and reactivates Akt20. Inhibiting PI3K raises oestrogen receptor transcriptional activity and receptor protein21, partly through a chromatin regulator22. Every trial in this class therefore pairs the inhibitor with endocrine therapy, and that is a mechanistic requirement rather than a convention.

Four randomised results define current practice, and each selected patients differently. BOLERO-2 added everolimus to exemestane without molecular selection23. Its final progression-free survival analysis confirmed the benefit24, and in patients aged 65 or older it remained effective with careful management of toxicity25. SOLAR-1 tested alpelisib in separate cohorts with and without a PIK3CA mutation and made the mutated cohort its primary population26. CAPItello-291 added capivasertib to fulvestrant without molecular selection and made the patients with a PIK3CA, AKT1 or PTEN alteration a co-primary population27. INAVO120 selected PIK3CA-mutated disease progressing during or shortly after adjuvant endocrine therapy, which is a clinical selection layered on a molecular one28,29.

Toxicity is the binding constraint and it is on-mechanism. Hyperglycaemia follows from inhibiting a pathway that mediates insulin signalling. Rash and stomatitis follow from inhibiting it in epithelium. Neither is avoidable by better patient selection, because the patients selected are those whose tumours depend on the pathway being inhibited. The practical limit is dose intensity maintained over months, and the clinical detail sits in Endocrine therapy with PI3K, AKT and mTOR pathway inhibition.

Selection has a measurement caveat. PIK3CA status from plasma and from archival tissue are not the same test, and matched white cell sequencing is needed to keep clonal haematopoiesis out of a plasma result30. PTEN loss is a convergent resistance mechanism as well as a selection criterion31, so its meaning depends on when it was measured.

5 · PARP inhibitors and DNA repair directed agents

Trapping and synthetic lethality are in PARP trapping and synthetic lethality. This section is about who the drugs are for and what the boundary of that group is.

Two randomised trials established activity in germline BRCA-mutated metastatic disease. OlympiAD compared olaparib with physician's choice chemotherapy32. EMBRACA compared talazoparib with chemotherapy33. OlympiA established adjuvant olaparib in high-risk germline BRCA-mutated early disease34.

The boundary of the group is the interesting part. TBCRC 048 tested olaparib beyond germline BRCA and found activity in germline PALB2 and in somatic BRCA1 or BRCA2 alterations35. The unifying property is loss of homologous recombination in the tumour, and germline status is a proxy for it rather than the thing itself.

The proxy problem is sharpest for platinum, and one trial settles how far genomic scores can be trusted. In unselected advanced triple-negative disease, carboplatin was not more active than docetaxel, with objective response rates of 31.4% against 34.0% in 376 patients. In the germline BRCA-mutated subgroup carboplatin doubled the response rate, at 68% against 33%, with an interaction p value of 0.01. Benefit was not seen in patients selected by BRCA1 methylation, by low BRCA1 messenger RNA, or by a high score on a commercial homologous recombination deficiency assay36.

Caution

A homologous recombination deficiency score measures accumulated genomic scarring, which is a record of past instability. Scars do not disappear when repair function is restored. In advanced triple-negative disease a high score did not identify platinum benefit while a germline mutation did36. The score answers a question about history and the drug needs an answer about the present. Reversion and other routes to restored tolerance are in Reversion mutations and other routes to PARP inhibitor resistance and PARP inhibitor and platinum resistance, including restoration of repair.

6 · Rare alteration directed and tumor-agnostic approaches

A tumour-agnostic claim is an inference, and its strength depends on how many histologies were tested and whether breast cancer was one of them. Three current examples differ sharply on that measure.

TRK fusion is the strongest case. Larotrectinib produced an overall response in 75% of 55 patients by independent review, with a 95% confidence interval of 61 to 85. Those patients carried 17 distinct tumour types and ranged in age from 4 months to 76 years37. Fusion-positive tumours are rare in breast cancer outside secretory carcinoma, so the practical issue is finding them rather than treating them.

Mismatch repair deficiency is the second. Pembrolizumab produced objective responses in 53% of patients and complete responses in 21%, across 12 tumour types38. The proposed mechanism is neoantigen supply, which makes the inference to other histologies mechanistically reasonable.

Tumour mutational burden is the weakest and it is the one most often applied loosely. One prospective biomarker analysis of a multi-cohort study set the threshold at 10 mutations per megabase. Objective responses occurred in 30 of 102 patients above it, which is 29%, and in 43 of 688 below it, which is 6%39. The ten enrolled cohorts were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid and vulvar. No breast cohort was included. A breast cohort has since reported in a different study. In the TAPUR basket trial, 28 patients with metastatic breast cancer and high tumour mutational burden received pembrolizumab, and disease control occurred in 37% and objective response in 21%40. No relationship was seen between progression-free survival and the burden itself. High tumour mutational burden is also uncommon in breast cancer41, so both the evidence and the eligible population are thin.

Other alterations have tumour-agnostic data and no breast-specific result. Erdafitinib was active across histologies with susceptible FGFR alterations in the RAGNAR basket study42. NTRK fusions are rare in common solid tumours and concentrated in rare ones, which is the pattern that makes secretory carcinoma the breast exception43.

HER2 mutation without amplification is the alteration-directed case specific to this disease. It is a different lesion from amplification, with allele-dependent sensitivity8,9, and it is missed by any assay that reports copy number alone.

7 · Combination strategies and overlapping toxicity

There are three defensible reasons to combine targeted agents, and only the first is a mechanism.

The first is to close the feedback loop the primary drug opens. mTOR inhibition reactivates Akt20, PI3K inhibition raises receptor signalling21, and HER-family inhibition is buffered by a shift in HER3 phosphorylation44. Each of those names its own partner, which is what makes the reasoning productive rather than combinatorial Pathway redundancy, feedback, and why single-node inhibition fails.

The second is to cover two dependencies that exist simultaneously. Hormone receptor positive, HER2-positive disease is the clean example, because oestrogen receptor signalling rises adaptively under anti-HER2 pressure45. Triple blockade with endocrine therapy, HER2 antibodies and a CDK4/6 inhibitor follows from that46, as does chemotherapy-free neoadjuvant treatment in selected disease47.

The third is depth of response where the endpoint requires it, which is mainly a neoadjuvant argument Neoadjuvant and adjuvant applications.

Overlapping toxicity decides most of what is feasible. Myelosuppression stacks, so a CDK4/6 inhibitor and a PARP inhibitor are difficult together. Diarrhoea stacks, so a pan-HER inhibitor and capecitabine constrain each other. Hyperglycaemia and QT prolongation do not stack with much, but each narrows the eligible population before the trial starts.

In practice

The comparison a combination has to win is not against the weaker single agent. It is against the sequence of the same two agents given one after the other.

Most combination trials do not run that comparison, so a positive combination result usually leaves open whether the benefit came from using both drugs or from using both drugs at once.

Where the mechanism is feedback relief, simultaneous administration is genuinely required, because the escape appears within weeks A working taxonomy, intrinsic, adaptive, and acquired resistance. Where the mechanism is covering two independent dependencies, sequence may cost little and will cost less toxicity.

8 · Cross-resistance between classes

Cross-resistance follows shared dependence. It does not follow shared indication, and the general argument is in Cross-resistance between classes and what it means for sequencing. What belongs here is the class-by-class version, because the strength of the prediction differs sharply between pairs.

Where the dependence is the same, the prediction is strong. Platinum and PARP inhibition both exploit defective homologous recombination, and a secondary mutation restoring the reading frame removes sensitivity to both48. Selection by germline mutation works for both and selection by genomic scar works for neither36.

Within the PI3K pathway the prediction is moderate. Alpelisib, capivasertib and inavolisib act at different nodes of one pathway, so a lesion that bypasses the pathway rather than the node, such as convergent PTEN loss, should affect all of them31. A lesion at the node should not.

Between HER2-directed antibodies and kinase inhibitors the prediction is weak, because the escape routes are demonstrably different12. Failure of one is poor evidence about the other, and that is a reason to try rather than a reason to expect.

Between endocrine therapy and CDK4/6 inhibition the relationship is asymmetric. An ESR1 mutation confers ligand independence, so it predicts failure of oestrogen deprivation as a class while leaving a receptor-directed drug with a target49. It does not predict failure of cell cycle inhibition, which depends on cyclin E1 and Rb rather than on ligand19,50.

Conjugates are the unsolved case and they are treated separately in Payload class, cross-resistance, and sequencing between conjugates.

Interplay

Every class in this chapter selects, and each selects for something different. An antibody selects for the compartment that does not display the antigen. A kinase inhibitor selects for the cell that does not depend on the kinase. A PARP inhibitor selects for the clone that restored repair. The composition of the tumour at progression was therefore partly fixed before the first dose, which is the heterogeneity argument arriving as a treatment-selection problem.

See Integrative biological interplay

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