Key takeaways:
- Including inavolisib to palbociclib and fulvestrant considerably prolonged OS for sure PIK3CA-mutated superior breast cancers.
- The routine additionally considerably delayed the time to chemotherapy.
The addition of inavolisib to palbociclib and fulvestrant considerably prolonged OS for sure sufferers with superior breast most cancers, based on outcomes of a randomized part 3 trial scheduled for presentation at ASCO annual assembly.
Adults with beforehand handled endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative illness who obtained inavolisib (Itovebi, Genentech) had a 33% decrease threat for loss of life in contrast with those that didn’t.
Information derived from Turner NC, et al. Summary 1003. Offered at: ASCO Annual Assembly; Might 30-June 3, 2024; Chicago.
“That is the primary time total survival has been considerably improved by a PI3K pathway-targeted drug,” Nicholas C. Turner, MD, PhD, FRCP, professor and director of scientific analysis and growth at The Royal Marsden NHS Basis Belief and Institute of Most cancers Analysis, mentioned throughout a press briefing.
INAVO120 trial
About 70% of all breast most cancers instances within the U.S. contain sufferers with HR-positive, HER2-negative illness, based on an ASCO press launch.
Roughly 40% of that group have a PIK3CA mutation, which prior analysis has proven is related to poor prognosis.
“In these cancers, the estrogen receptor, CDK4/6, and PI3K signaling pathways are key to most cancers development and survival,” Turner mentioned. “Focusing on these three pathways without delay with totally different medicine can improve responses to the remedy and in addition delay resistance. Beforehand, it has not been doable to mix PI3K inhibitors with CDK4/6 inhibitors as a consequence of unintended effects.”
In October 2024, the FDA authorized inavolisib, a PIK3 inhibitor, plus palbociclib (Ibrance, Pfizer) and fulvestrant as remedy for sufferers with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, HER2-negative superior breast most cancers whose illness recurred on or after ending adjuvant endocrine remedy.
The FDA primarily based its approval on prior findings of INAVO120, which included 325 sufferers (median age, 54 years; vary, 27-79; 98.2% girls; 58.8% white; 38.2% Asian) who had illness recurrence inside 12 months of adjuvant endocrine remedy and had not obtained prior systemic remedy for regionally superior or metastatic illness.
Researchers randomly assigned sufferers 1:1 to 9 mg oral inavolisib or placebo as soon as every day, plus 125 mg oral palbociclib for 21 straight days adopted by 7 days off. Sufferers additionally obtained 500 mg fulvestrant administered intramuscularly on days 1 and 15 of the primary 28-day cycle, adopted by day 1 of each subsequent cycle.
The inavolisib arm had 161 sufferers and the placebo had 164.
Healio beforehand reported part 3 outcomes, which confirmed adults within the inavolisib arm had a considerably longer PFS (median, 15 months vs. 7.3 months; stratified HR = 0.43; 95% CI, 0.32-0.59) and period of response (18.4 months vs. 9.6 months; HR = 0.57; 95% CI, 0.33-0.99).
PFS served as the first endpoint. OS, goal response price, greatest total response, scientific profit price, period of response and patient-reported outcomes served as secondary endpoints.
‘Huge step ahead’
At median follow-up of 34.2 months, sufferers within the inavolisib arm had considerably longer median OS (34 months vs. 27 months; stratified HR = 0.67; 95% CI, 0.48-0.94) in contrast with these within the placebo group.
Those that obtained inavolisib additionally had a better chance of being alive 6 months after remedy (96.8% vs. 90.1%), in addition to at 1 12 months (87% vs. 76.7%), 1.5 years (74.3% vs. 67.2%), 2 years (65.8% vs. 56.3%) and a pair of.5 years (56.5% vs. 46.3%).
Moreover, the investigative arm had a superior goal response price (62.7% vs. 28%) and began chemotherapy later (median, 35.6 months vs. 12.6 months; stratified HR = 0.43; 95% CI, 0.3-0.6).
Researchers additionally discovered members who obtained inavolisib had a “substantial” PFS enchancment from the earlier replace, Turner mentioned. Median PFS improved from 15 months to 17.2 months within the inavolisib arm however didn’t change for the placebo arm (7.3). The inavolisib arm had a 58% longer PFS than the placebo group (stratified HR = 0.42; 95% CI, 0.32-0.55).
Sufferers who obtained inavolisib had greater charges of grade 3 or 4 antagonistic occasions (90.7% vs. 84.7%), critical antagonistic occasions (27.3% vs. 13.5%) and any-grade hyperglycemia (63.4% vs. 13.5%).
In addition they discontinued remedy as a consequence of antagonistic occasions (6.8% vs. 0.6%) or lowered dose (14.9% vs. 3.7%) extra typically.
Turner described the security profile as “manageable,” however cautioned that inavolisib is just not with out toxicities, highlighting hyperglycemia, rash and diarrhea.
“We’ve been making an attempt to develop PI3K inhibitors for a few years, and what we’ve realized about it’s the extra particular and selective your drug can get for the mutant protein, the more practical it’s as a result of it minimizes unintended effects,” he mentioned. “Inavolisib targets PI3K, but it surely selectively degrades the mutant kinase. This probably makes it extra selective for the breast most cancers that’s acquired the PI3K mutation, in order that maximizes your means to hit PI3K within the tumor, comparatively sparing regular cells within the physique and lowering unintended effects.”
Julie R. Gralow, MD, FACP, FASCO, ASCO chief medical officer, mentioned she was “impressed’ how the triplet routine delayed the necessity for chemotherapy.
Within the press launch, Jane L. Meisel, MD, FASCO, ASCO skilled and co-director of breast medical oncology on the Winship Most cancers Institute of Emory College College of Drugs, referred to as the outcomes a “huge step ahead for these sufferers.”
She added, “This research illustrates the significance of genomic testing on the time of analysis of hormone receptor-positive metastatic breast most cancers, in order that sufferers with PIK3CA mutations who qualify for this strategy will be readily recognized.”
References:
Perspective
Iris Zhi, MD, PhD
The general survival outcomes of INAVO120 demonstrated a 7-month enchancment within the inavolisib group in contrast with the placebo group. This discovering is according to the beforehand reported PFS profit of seven.5 months, which was the research’s main endpoint. This end result reinforces the survival advantage of including inavolisib to the mixture of palbociclib with fulvestrant within the frontline setting for high-risk sufferers with PIK3CA-mutated hormone receptor-positive, HER2-negative breast most cancers. It’s practice-changing.
A extra thrilling discovering is the considerably delayed time to chemotherapy: 35.6 months with triplet remedy vs. 12.6 months within the placebo group. This discovering highlights the advantage of using PIK3CA inhibitors within the first-line setting, extending past the development of illness.
Triplet remedy (inavolisib/palbociclib/fulvestrant) must be thought of the standard-of-care, first-line remedy for sufferers with hormone receptor-positive, HER2-negative, PIK3CA-mutated regionally superior or metastatic breast most cancers. As anticipated, inavolisib is related to hyperglycemia (63.4%), and 6.8% sufferers discontinued inavolisib as a consequence of unintended effects in contrast with the placebo group (0.6%).
Routine testing for PIK3CA mutations amongst sufferers with hormonal receptor-positive metastatic breast most cancers is crucial. We additionally want to higher handle inavolisib-related unintended effects so sufferers can totally profit from it.
Iris Zhi, MD, PhD
Perlmutter Most cancers Heart at NYU Langone Hospital Lengthy Island
Disclosures: Zhi experiences no related monetary disclosures.
Sources/Disclosures
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Turner NC, et al. Summary 1003. Offered at: ASCO Annual Assembly; Might 30-June 3, 2024; Chicago.
Disclosures:
Turner experiences consultancy or advisory board for AstraZeneca, Actual Sciences, Gilead Sciences, GlaxoSmithKline, Guardant Well being; Inivata, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Relay Therapeutics, Repare Therapeutics and Roche; and analysis funding from AstraZeneca (Inst), Guardant Well being (Inst), Inivata (Inst), InVitae (Inst), Merck Sharpe and Dohme (Inst), Natera (Inst), Personalis (Inst), Pfizer (Inst) and Roche (Inst). Please see the summary for all different authors’ related monetary disclosures.
