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Recommendation of the President – Opdivo (nivolumab) in combination with Yervoy (ipilimumab)

On 22 July 2022 the President of the Agency for Health Technology Assessment and Tariff System issued the following recommendation:

 

Recommendation No. 68/2022 of 22 July 2022 of the President of the Agency for Health Technology Assessment and Tariff System) on the evaluation of Opdivo (nivolumab) in combination with Yervoy (ipilimumab) as part of the drug programme ,,Treatment of non-small-cell or small-cell lung cancer (ICD-10 C34) and treatment of pleural mesothelioma (ICD-10 C45)”.

 

The President of the Agency recommends the reimbursement of Opdivo (nivolumab) in combination with Yervoy (ipilimumab) under the drug program “Treatment of non-small cell or small cell lung cancer (ICD-10 C34) and treatment of pleural mesothelioma (ICD-10 C45)”, provided that [information protected as a trade secret] and the criteria in the description of the drug program are aligned.

 

Grounds for the recommendation 

The efficacy assessment of the technology covered by the application is based on a direct comparison of nivolumab in combination with ipilimumab (NIV+IPI) and standard chemotherapy (pemetrexed in combination with cisplatin or carboplatin, CHT) as first-line treatment in patients with malignant pleural mesothelioma. Statistically significant differences were obtained in favor of NIV+IPI in terms of overall survival (during a follow-up period of 43.1 months: 18.1 months vs. 14.1 months), patient overall survival rate at 1 year, 2 and 3 years (68% vs. 58%, 41% vs. 27% and 23% vs. 15% of patients, respectively) or progression-free survival rate at 2 and 3 years (18% vs. 7% and 14% vs. 1%, respectively).

A statistically significantly longer overall survival in the NIV+IPI group in comparison to the standard treatment group (HR = 0.46 [95% CI: 0.31; 0.68]) and improvement of progression-free survival (HR = 0.58 [95% CI: 0.38–0.90]) were observed for patients with non-epithelioid mesothelioma. However, for patients with epithelioid mesothelioma, no statistically significant difference was found in terms of overall survival and progression-free survival in the NIV+IPI group in comparison to the standard therapy group (HR = 1.14 [95% CI: 0.92–1.41]).

No statistically significant differences were reported in terms of progression-free survival between the entire NIV+IPI patient group and the CHT patient group or in terms of the patients achieving response or partial response.

Moreover, it should be noted that during a follow-up period of 29.7 months, a statistically significantly lower chance of achieving disease control (OR = 0.57 [95% CI: 0.38; 0.87]) was reported for patients treated with nivolumab in combination with ipilimumab. Disease progression was reported 4.5 times more often in this group of patients versus the CHT group (OR = 4.56 [95% CI: 2.48; 8.40]).

The above results justify [information protected as a trade secret].

[Information protected as a trade secret].

Despite the uncertainties associated with the study not being blinded, which may affect the quality of life results collected using questionnaires, it should be noted that, due to the nature of the indication, the risk connected with the impact on survival-related endpoints is low.

The adverse reaction profile was also considered. The use of NIV+IPI was associated with a statistically significantly higher incidence of a portion of grade 1 and 2 treatment-emergent adverse events (including diarrhea, pruritus, rash, hypothyroidism), all-grade and grade 3 and 4 serious treatment-emergent adverse events (colitis), as well as all-grade and grade 3 and 4 adverse events leading to treatment discontinuation.

Due to the above-mentioned limitations of the efficacy of NIV+IPI combination treatment for epithelioid pleural mesothelioma, it is reasonable to equalize the NIV+IPI therapy costs with the costs of standard therapy in the population for which the treatment does not add greater value than the standard therapy (the above-mentioned argument was raised in two recommendations [ZIN 2021 and G-BA 2021], which emphasized that better results in an RCT were obtained in a subgroup of patients with non-epithelioid tumor histology (statistically significant difference in terms of OS in favor of the proposed therapy), while no difference was demonstrated between the study arms for the epithelioid type (no significant difference in terms of OS and statistically significantly higher incidence of serious adverse events in the Opdivo + Yervoy arm).

The ZIN 2021 recommendation also suggested that due to the lack of significant efficacy differences in patients with an epithelioid tumor, the cost of the proposed therapy for this group of patients should not be higher than the cost of the standard therapy.

According to the cost-utility analysis, using nivolumab in combination with ipilimumab in comparison to pemetrexed in combination with cisplatin or carboplatin is [information protected as a trade secret] from the public payer’s perspective. The estimated ICUR for the comparison of NIV+IPI vs. CHT was  [information protected as a trade secret].

[Information protected as a trade secret]

Moreover, [information protected as a trade secret] from the perspective of the National Health Fund [information protected as a trade secret]. Uncertainties in this aspect of assessment should result in [information protected as a trade secret].

The budget impact analysis indicated that reimbursement of the drug would involve [information protected as a trade secret] for the treatment of patients in the target population. [information protected as a trade secret].

There is also an uncertainty associated with the applicant underestimating the population size, [information protected as a trade secret]. The Agency’s own estimations indicate that [information protected as a trade secret] public payer’s expenses [information protected as a trade secret].

To conclude, the reimbursement of the medicinal products under assessment is justified, as it may lead to meeting the patients’ health needs. However, there is a number of uncertainties associated with the costs of therapy as compared to the comparator, as well as those associated with the target population size and, consequently, with the total cost of therapy. Potential reimbursement would have to involve [information protected as a trade secret] and aligning the provisions of the existing drug program B.6. “Treatment of non-small cell or small cell lung cancer (ICD-10 C34)” with the extended drug program “Treatment of non-small cell or small cell lung cancer (ICD-10 C34) and treatment of pleural mesothelioma (ICD-10 C45).”

 

Publication in Public Information Bulletin (BIP)