Palbociclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy

3.1 People with advanced breast cancer who have had endocrine therapy are eligible for the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib or ribociclib, in combination with fulvestrant, if exemestane plus everolimus is the most appropriate alternative (see NICE's technology appraisal guidance on abemaciclib and ribociclib). Patient experts said that these treatments can delay disease progression and delay or avoid the need for chemotherapy. Patient experts noted that they value a choice of treatment options because CDK4/6 inhibitors have different side effect profiles. Choice would give people the option to change to a different treatment if needed. Patient experts noted that the side effect profile of palbociclib is more similar to ribociclib than abemaciclib, but unlike ribociclib, palbociclib does not need any ECG monitoring. The committee concluded that having a choice of treatments is valued by people with advanced breast cancer.

3.2 PALOMA-3 is a multicentre double-blind randomised placebo-controlled trial comparing palbociclib plus fulvestrant (n=347) with placebo plus fulvestrant (n=174) in adults with hormone receptor-positive, HER2-negative advanced breast cancer. An additional 28 months of overall survival data were collected in the ongoing trial while palbociclib was also available to people through the Cancer Drugs Fund. After a median follow-up of 73.3 months in the trial, median overall survival was 6.8 months longer in people who had palbociclib plus fulvestrant compared with those who had placebo plus fulvestrant (median 34.8 months for palbociclib plus fulvestrant compared with 28.0 months for placebo plus fulvestrant [HR 0.81; 95% CI 0.65 to 0.99, p=0.02]). The committee noted that there was a relatively long follow-up period in PALOMA-3. The EAG noted that people in the trial may have had more previous treatments than people seen in NHS clinical practice, but considered that the results are generalisable to the NHS. The committee concluded that the results from PALOMA-3 are relevant to the NHS and the trial has a long follow-up period.

3.3 Public Health England provided observational data from the SACT dataset for 1,140 people who had palbociclib plus fulvestrant through the Cancer Drugs Fund. Median follow-up was 10 months. Median treatment duration with palbociclib plus fulvestrant was 9.4 months and median overall survival was not yet reached. At 6 months, 88% of people taking palbociclib plus fulvestrant were alive; at 12 months, 75% were alive; and at 18 months, 63% were alive. The committee noted that equivalent overall survival rates were seen with abemaciclib plus fulvestrant at 6 and 12 months in SACT. It noted that the SACT dataset did not directly compare palbociclib plus fulvestrant with abemaciclib plus fulvestrant but the findings showing similar efficacy of the 2 treatments in NHS clinical practice were reassuring. The committee concluded that a large SACT dataset supports the clinical effectiveness of palbociclib plus fulvestrant.

3.4 Abemaciclib and ribociclib are CDK4/6 inhibitors recommended by NICE for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. Palbociclib is another CDK4/6 inhibitor that works in a similar way to abemaciclib and ribociclib. The EAG's clinical advisers noted that the 3 drugs have the same primary mechanism although with some differences in individual inhibition of CDK4 and CDK6 in laboratory studies. They also noted differences in dosing schedules, serum concentration and toxicity. All 3 CDK4/6 inhibitors are administered orally. Palbociclib and ribociclib are given once daily for 21 days of a 28‑day cycle. Abemaciclib is given twice daily for the whole cycle. All are combined with fulvestrant, which is given by intramuscular injection, twice in the first month, followed by once monthly. The committee concluded that abemaciclib plus fulvestrant and ribociclib plus fulvestrant are appropriate comparators for palbociclib plus fulvestrant.

3.5 The pivotal clinical trials of abemaciclib plus fulvestrant and ribociclib plus fulvestrant are MONARCH 2 (n=669) and MONALEESA-3 (n=726). As in PALOMA-3 (see section 3.2), these trials compared a CDK4/6 inhibitor plus fulvestrant with placebo plus fulvestrant. All 3 trials had investigator-assessed progression-free survival as the primary endpoint. The committee considered that MONARCH 2 and MONALEESA-3 provided suitable clinical evidence for a comparison with PALOMA-3. People in PALOMA-3 and MONARCH 2 could be in any stage of menopause, while those in MONALEESA-3 were in postmenopause. However, in PALOMA‑3 and MONARCH 2, people who were in premenopause or perimenopause had a luteinising hormone-releasing hormone agonist to make them functionally in postmenopause. The EAG noted that people in PALOMA-3 had more previous chemotherapy in the metastatic setting than the other 2 trials. The committee also noted that people in PALOMA‑3 were younger (75% aged under 65 years) than those in MONARCH 2 (63% aged under 65 years) or MONALEESA-3 (53% aged under 65 years). The committee concluded that MONARCH 2 and MONALEESA-3 can be compared with PALOMA-3, although there are some differences between the 3 trial populations.

3.6 The results of PALOMA-3, MONARCH 2 and MONALEESA-3 show that palbociclib plus fulvestrant, abemaciclib plus fulvestrant and ribociclib plus fulvestrant improve progression‑free survival and overall survival compared with placebo plus fulvestrant. The EAG stated that the hazard ratios for these outcomes were similar for the 3 treatments and the committee was aware that follow up was longer in the palbociclib trial than the others. Only PALOMA-3 and MONALEESA-3 collected data on subsequent therapy. This showed that most people had a follow-on therapy. The EAG stated that some people had a subsequent CDK4/6 inhibitor which is not standard NHS practice. However, the committee noted that this was more common in people who had placebo plus fulvestrant in the trial and had not had a CDK4/6 inhibitor before. The committee concluded that evidence from the 3 clinical trials suggests that palbociclib, abemaciclib and ribociclib, all in combination with fulvestrant, are likely to provide similar health benefits in terms of progression-free and overall survival.

3.7 The company noted that the 3 CDK4/6 inhibitors have a broadly similar profile of grade 3 or higher adverse events. But there are important differences in some low grade adverse events. Neutropenia is less common and lower grade with abemaciclib plus fulvestrant than with palbociclib plus fulvestrant or ribociclib plus fulvestrant. Any grade diarrhoea is more common with abemaciclib plus fulvestrant (87%) than with palbociclib plus fulvestrant or ribociclib plus fulvestrant (both less than 30%). The EAG noted that the lower rates of diarrhoea seen with palbociclib plus fulvestrant than with abemaciclib plus fulvestrant have the potential to improve health-related quality of life. The Cancer Drugs Fund clinical lead noted that diarrhoea has a direct impact on people having treatment. Neutropenia is a toxicity detected through regular blood testing but it may not affect the person having treatment or cause symptoms. The committee recalled that people with advanced breast cancer value choice in treatments and the option to change to a different treatment if needed (see section 3.1). The committee concluded that there are some differences in low grade adverse events between palbociclib, abemaciclib and ribociclib that may impact treatment choice.

3.8 The company presented matching-adjusted indirect treatment comparisons (MAICs) of palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant and ribociclib plus fulvestrant. These used latest survival data from the 3 pivotal trials (see section 3.6). In the MAICs, the PALOMA-3 population was statistically adjusted to resemble the MONARCH 2 and MONALEESA-3 populations. This was to predict the treatment effect if palbociclib plus fulvestrant had been evaluated in these populations. The EAG agreed with the company's approach to account for differences between the 3 trial populations (see section 3.5). It considered that the MAICs were well designed. The MAICs of palbociclib plus fulvestrant and abemaciclib plus fulvestrant included up to 12 potential treatment effect modifiers. The results suggested no statistically significant difference in progression-free survival or overall survival with palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant. The committee noted that the MAICs suggest that the clinical efficacy of palbociclib plus fulvestrant is similar to abemaciclib plus fulvestrant. The MAICs of palbociclib plus fulvestrant and ribociclib plus fulvestrant included up to 13 potential treatment effect modifiers. The results suggested no statistically significant difference in overall survival with palbociclib plus fulvestrant compared with abemaciclib plus fulvestrant. However, some of the MAICs for progression-free survival, including when all effect modifiers were considered, suggested a statistically significant difference in favour of palbociclib plus fulvestrant. The committee noted that the MAICs suggest that the clinical efficacy of palbociclib plus fulvestrant is similar to or better than that of ribociclib plus fulvestrant. The committee concluded that the well-designed MAICs suggest that palbociclib plus fulvestrant is similar to or better than the comparators.

3.9 The company presented a cost-comparison analysis that included the costs of drug acquisition, administration, monitoring and adverse events. The company base case assumed a 40‑year time horizon. Adverse event rates were assumed to vary by treatment and were based on publicly available data. Monitoring differed by treatment, with:

3.10 The committee did not identify any equality issues.