This question was discussed at the recent G-BA meeting on 2 September 2021.
Previously, the G-BA had decided on the following procedural rules:
- Products used off-label can be considered as ACTs.
- However, where a product with a license for the relevant indication exists, this would be preferred and should be chosen instead.
- If the available evidence suggests that an off-label drug is the preferred treatment choice over licensed treatment options, then the off-label drug can be included in the ACT alongside the licensed drugs.
In the context of the assessment of tucatinib for HER2-positive breast cancer, the G-BA now discussed whether this preference for an off-label drug exists. This decision is very important for the early benefit assessment of tucatinib since it determines whether the study HER2CLIMB comparing with the off-label drug is accepted and included in the early benefit assessment or not.
ACT for tucatinib
Tucatinib in combination with trastuzumab and capecitabine is indicated in the treatment of adult patients with HER2-positive locally advanced or metastatic breast cancer who have previously received at least 2 treatment regimens directed against HER2. The G-BA had previously determined that the following ACT:
- Lapatinib in combination with capecitabine or
- Lapatinib in combination with trastuzumab (for patients with HR-negative breast cancer).
The G-BA now debated whether the ACT should be changed to therapy according to the treating physician, i.e. physician’s choice, which includes trastuzumab in combination with capecitabine as an option.
Position of KBV
The KBV supported the inclusion of trastuzumab in combination with capecitabine in the ACT. In their opinion, there is sufficient evidence that the combination is an important treatment option in clinical practice. They made the following arguments:
- There is no common treatment standard across all patients.
- The CEREBEL study for lapatinib showed that trastuzumab + chemotherapy was more effective than lapatinib + chemotherapy.
- In addition, the EPAR mentions the use of the trastuzumab combination as an option for third-ine treatment of HER2-positive breast cancer.
- Furthermore, ASCO guidelines state that further treatment with HER2-based therapy in combination with chemotherapy is an option, although this is based on only limited evidence. The S3 clinical guideline of the AMWF does not cover third-line treatment.
Position of GKV-SV
The GKV-SV instead argued that the off-label use of trastuzumab in combination with capecitabine should NOT be considered as part of the ACT. They did not feel that the available evidence demonstrates a preference for its use. Their position was supported by the following:
- A German PRAEGNANT registry data submitted by the manufacturer only reported a 20% use of the trastuzumab + capecitabine combination.
- In addition, the German clinical S3 guidelines don’t recommend the use of trastuzumab + capecitabine in third-line treatment. The combination is merely mentioned as a side note.
- While clinical experts have confirmed that trastuzumab + capecitabine is used in clinical practice, they did not support the notion that this combination would be preferred to other options.
- The CEREBEL study that was cited by the KBV did not include patients in third-line treatment. Also the medical experts considered trastuzumab + capecitabine only as efficacious as the other options, but not more efficacious.
Position of DKG
The DKG underlined that the focus for any decision should always be on the patient. Therefore, they agreed with the KBV and supported the extension of the ACT.
The HER2CLIMB study demonstrated an overall survival advantage for tucatinib. The median OS was increased by 4.5 months, which is hugely relevant for patients. Since this study compared with an off-label drug that is used in clinical practice, the DKG supported widening the ACT to physician’s choice.
Position of patient representation
The patient representative also supported the view that the ACT should be defined as physician’s choice, as this would reflect all treatment options used in clinical practice. Given that the indication targets third-line treatment, it is not expected that evidence recommending one specific treatment option would emerge.
Voting to allow off-label drug as appropriate comparator
The majority voted to add trastuzumab in combination with capecitabine as an additional third ACT option. This change acknowledges the opinions of medical societies on real-world clinical practice and the current therapy recommendations.
Additional benefit resolution
The inclusion of the off-label option in the ACT had a big impact on the overall resolution.
With trastuzumab in combination with capecitabine seen as an ACT option, the study HER2CLIMB was accepted and included in the early benefit assessment. This RCT demonstrated a significant extension of overall survival, and no disadvantage in terms of morbidity and side effects.
The acceptance of this study for the early benefit assessment changed the decision from “Additional benefit not proven” to “Hint of considerable additional benefit“.
The final G-BA resolution in German can be found here, and the English translation is expected to become available in October 2021. If you are interested in following the discussion between the G-BA members, you can watch it under the 77. Public meeting (time: 21:30 until 42:27).