NEWS

Dr Sanjeev Kumar- Medical Oncologist, Chris O’Brien Lifehouse and RPAH 

ASBD Director

It was a busy and diverse SABCS this year! Focussing on therapeutic updates that have the potential to change our therapeutic landscape, here are few abstracts that caught my attention.

GS01-01 (Checkmate-7FL)

Both Keynote-756 and Checkmate-7FL explore the role of augmenting neoadjuvant chemotherapy with immunotherapy in high risk HR+ breast cancer, based on preceding data from the I-SPY2 study. pCR data for both studies was presented at ESMO 2023, confirming promising improvements in pCR with the addition of pembrolizumab and nivolumab respectively. At SABCS 2023, biomarker analyses was presented for both studies to assist in improving our selection of patients for this strategy.

In Checkmate-7FL, there was clear benefit with the addition of nivolumab in patients who were PD-L1+, in particular those with higher 28-8 CPS scores (close to an unparalleled 80% in patients with a 28-8 CPS score of ≥20). Greater benefits were also seen with lower ER (<50%) and PR (<10%) expression, sTIL% carried both prognostic and predictive value, but interestingly and surprisingly Ki67 did not correlate with pCR.

GS01-02 (Keynote-756)

Keynote-756 was able to recruit double the number of patients, and will be powered to detect differences in EFS. The addition of pembrolizumab improved pCR regardless of whether patients had completed the full chemotherapy schedule, or had Stage II or III disease. Benefit was greater in the node positive population, and less clear in patients with a PD-L1 22C3 CPS score ≤1% (with a smaller delta and wide confidence intervals), in particular those with ER≥10%. Once again, benefit was seen to increase with higher CPS scores, regardless of ER positivity. sTIL% data is awaited.

So while we now have some predictive biomarkers of immunotherapy response based on pCR in early, high risk HR+/HER2- breast cancer, given the potential drug and financial toxicities of this strategy, we need to wait and see if pCR translates to an EFS benefit and whether these biomarkers correlate with the EFS data. We also need to understand whether the addition of immunotherapy will provide additional benefit to other strategies in high risk HR+/HER2- breast cancer, such as adjuvant CDK4/6-inhibition.

GS01-03 (IMpassion030/ALEXANDRA study)

Following on from the practice-changing Keynote-522 study, Impassion030 answers the questions of whether the timing of immunotherapy administration in early triple negative breast cancer is important, and if adjuvant-only immunotherapy could be beneficial. At a median follow up of 25 months, futility was declared as there was no statistically significant difference in iDFS benefit, regardless of PDL1 status, emphasising that the use of neoadjuvant immunotherapy is clearly preferred.

It is likely that the presence of tumour in situ with neoadjuvant administration of immunotherapy triggers the activation of a more diverse T cell repertoire with more robust anti-tumour potential, compared to an upfront surgical approach.

GS03-12 (Katherine)

We were updated on results from the practice-changing Katherine study at a median follow up of 8.4 months. In this study, recruited patients had residual disease after neoadjuvant therapy for early HER2+ breast cancer, but only ~18% had received dual neoadjuvant HER2-directed therapy (trastuzumab and pertuzumab) and ~3/4 had received prior anthracycline, less accurately reflecting current trends in neoadjuvant systemic therapy administration.

However, excitingly, iDFS benefits for adjuvant TDM1 vs. trastuzumab had increased from 11.3% previously reported at 3 years, to 13.7% at 7 years, with all subgroups benefitting from TDM1. A nearly 5% OS benefit was also reported at 7 years, with a final OS analysis planned at 12 years. Cardiac toxicity remained rare in both arms of the study.

Unsurprisingly, recurrences were mostly distant. But while it is clear that adjuvant TDM1 is highly effective at reducing the risk of non-CNS recurrence, it is not significantly more effective than trastuzumab alone at preventing CNS recurrence. We therefore await the results of both the COMPASS Residual Disease trial (adjuvant TDM1 + tucatinib vs. TDM1 + placebo) as well as the DESTINY-Breast05 study (adjuvant T-DXd vs. TDM1).

GS01-10 (HER2CLIMB-02)

Following on from the HER2CLIMB study, the HER2CLIMB-02 study again acknowledges that 50% of patients with HER2+ metastatic breast cancer develop brain metastases, due to inherent neurotropism of HER2+ breast cancer cells, and the CNS being a sanctuary site for metastases in early HER2+ breast cancer due to inadequate anti-HER2 agent penetration of the intact blood brain barrier in this setting. HER2CLIMB-02 assessed the efficacy of TDM1 + tucatinib vs. TDM1 alone in a contemporary population of patients who had predominantly received prior pertuzumab, and included 44% of patients with brain metastases (~50% of these active or progressing). Patients had received a median of 1 prior line of systemic therapy for metastatic disease.

A promising improvement in mPFS was observed in both the ITT population as well as the cohort of patients harbouring brain metastases with the addition of tucatinib to TDM1, but higher treatment discontinuation rates were observed with HER2CLIMB-02 compared to HER2CLIMB, with higher rates of nausea, diarrhoea and elevated transaminases. It is also difficult to view these results in the context of Destiny Breast-03, where T-DXd (which also has demonstrated intracranial activity) was observed to quadruple the mPFS compared to TDM1, firmly establishing this ADC as our favoured 2^nd line treatment for metastatic HER2+ breast cancer. While it is unlikely that HER2CLIMB-02 will change the current algorithm, the study reinforces the role of tucatinib in the treatment of HER2+ breast cancer, with promising intracranial activity.

GS01-12 (MONARCH 3)

The long-awaited updated primary and secondary endpoint data from this 1^st line study of abemaciclib in combination with a non-steroidal aromatase inhibitor, compared to a non-steroidal aromatase inhibitor alone in postmenopausal women with HR+ HER2- metastatic breast cancer was presented following 8.1 years of follow up. Updated mPFS data again confirmed doubling of mPFS (29 vs. 14.8 months), and it is very promising to see that >23% patients remain progression free at 6 years. Very pronounced improvements in Overall Survival (OS- a secondary endpoint) were observed (66.8 months vs 53.7 months) with dramatic separation of the survival curves, and numerically this was the greatest absolute difference in OS of any of the CDK4/6i studies. However, these OS results were unexpectedly not statistically significant, likely secondary to the smaller recruitment numbers compared to the MONALEESA studies, the 2:1 randomisation, and the higher proportion of 2^nd line use of CDK4/6-inhibtors in the control arm. I therefore don’t feel that this OS data with a p-value that did not reach the threshold of statistical significance should impact the utility of abemaciclib in treating patients with HR+ metastatic breast cancer.

GS03-13 (INAVO120)

The INAVO120 study was presented as a late-breaking abstract at SABCS. This posed the question of whether a triplet combinatorial strategy could be used to overcome endocrine resistance by exploiting cross-talk between ER, PI3K and CDK4/6 pathways, a strategy that has been plagued by toxicity issues in preceding studies. Inavolisib is a highly potent and selective PI3Kalpha inhibitor which in preclinical models demonstrates more on-target potency than alpelisib. Poor prognostic HR+, PIK3CA-mutated (by ctDNA) patients with good glycaemic control who had either progressed during adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy were recruited. This was a relatively young cohort of patients (median age 53), 80% of whom had visceral disease (50% hepatic), 1/3 were considered primary endocrine-resistant and 2/3 were considered secondary endocrine-resistant, and ~83% had received prior (neo)adjuvant chemotherapy.

Excitingly, the addition of inavolisib to Palbociclib + fulvestrant in this carefully selected, high risk population essentially doubled PFS at a median follow up of 21.3 months (PFS 15 vs. 7.3 months, HR 0.43), with a more doubling of objective response rate and an immature trend towards an overall survival benefit. The initial steep drop off in the Kaplan-Meier curves seen in similar studies of endocrine-resistant patients was reassuringly not observed in the triplet combination arm, theorising that this combination may indeed be potentially efficacious in overcoming endocrine resistance. While more significant rates of stomatitis were observed, this could be prevented going forward with prophylactic steroid mouthwash, and overall less high-grade hyperglycaemia, diarrhoea, rash and nausea were observed compared to studies of alpelisib. It will be fascinating to compare the outcome of INAVO120 to the ongoing CAPItello-292.