Avelumab (1) – Bavencio®

• Clinical trials
  • The JAVELIN trial is an ongoing, single-arm, open-label, multicentre Phase II trial enrolling patients with histologically confirmed metastatic Merkel cell carcinoma.
  • The ongoing Study Part B is investigating avelumab in patients with metastatic disease who have not previously received chemotherapy.
  • In study arm A, the safety and efficacy of avelumab are being investigated in 88 patients with disease progression following at least one course of chemotherapy in the metastatic stage.

a) For patients with metastatic disease who have not received prior chemotherapy

• Consequently, given the currently limited data available, the G-BA classifies the extent of the additional benefit of avelumab, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease is non-quantifiable.
• An additional benefit exists in accordance with Section 35a(1), sentence 11, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • In the JAVLIN study, overall survival was defined as the time between the first administration of avelumab and death from any cause.
  • For patients who had not received prior chemotherapy, the median overall survival had not yet been reached as at the data cut-off date of 26 September 2017, with a median follow-up period of 6.7 months.
  • At that time, 78.4% of patients were still alive.
• Morbidity – Tumour response
  • In the JAVELIN trial, tumour response was assessed, amongst other things, using the endpoints ‘Confirmed Best Response’ and ‘Objective Response Rate’.
  • Tumour response was assessed in accordance with the RECIST criteria. In the case of skin lesions, assessment was also carried out using colour photographs with the aid of a suitable scale.
  • The assessment of disease progression based on the RECIST criteria was therefore not symptom-based, but was carried out exclusively using imaging procedures.
  • The pharmaceutical manufacturer provided no information regarding the characteristics of the skin lesions present at the start of the study (e.g. location, extent of the lesion, degree of ulceration in patients who presented with ulceration at baseline) nor regarding changes to these lesions during treatment with avelumab (e.g. extent of the lesion or degree of ulceration). Essential information for interpreting the tumour response results is therefore lacking.
  • Overall, the tumour response endpoints in this assessment, as currently defined, are not classified as patient-relevant endpoints.
  • There is no validation of tumour response as a surrogate parameter for patient-relevant endpoints, e.g. mortality.
• Morbidity – Progression-free survival (PFS)
  • PFS was defined as the time from the start of treatment to disease progression or death from any cause, whichever occurred first. Evidence of disease progression was assessed according to the RECIST criteria.
  • As of the data cut-off date of 26 September 2017, the median PFS for patients without prior chemotherapy was 4.2 months (95% confidence interval (CI): 2.9; 12.7).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint had already been assessed as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of the morbidity endpoint was assessed, in accordance with its operationalisation, not on the basis of symptoms but exclusively by means of imaging procedures.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding the extent of the additional benefit remains unaffected by this.
• Quality of life – FACT-M
  • Health-related quality of life was assessed using the FACT-M questionnaire. This was administered at baseline, every 6 weeks during treatment, and 28 days after the last treatment.
  • The limitations mentioned in connection with the EQ-5D VAS – namely the lack of reference to the ITT population and the analyses of patients who did not show any relevant deterioration in health status at any point after the start of treatment – apply equally to the FACT-M. Consequently, in line with the comments in the ‘Health status’ section, the results on health-related quality of life are not considered usable overall.
• Side effects
  • Adverse events occurred at least once in almost every patient as of the data cut-off date of 26 September 2017.
  • Serious adverse events (SAEs) were observed in 36.5% of patients, whilst severe adverse events (CTCAE grade ≥ 3) occurred in 37.8% of patients. AE leading to discontinuation of the study medication occurred in 18.9% of patients. Among AEs of particular interest , immune-mediated AEs were observed in 17.6% of patients and infusion-related reactions in 27.0% of patients.
• Overall assessment
  • For the benefit assessment of avelumab in the treatment of adults with metastatic Merkel cell carcinoma, results are available for patients without prior chemotherapy in the metastatic stage across the endpoint categories of mortality (overall survival), Morbidity, quality of life and side effects from the uncontrolled clinical study JAVELIN Merkel 200.
  • The historical data submitted by the pharmaceutical manufacturer for a naive indirect comparison in the endpoint categories of mortality and morbidity are not considered suitable for demonstrating additional benefit, in particular due to the insufficient comparability of the study populations.
  • Due to the single-arm study design and the unsuitable historical control, a comparative assessment of the study results is not possible.
  • In the present case, the decisive factor is the lack of meaningful evidence, which does not permit a valid assessment of the results.
  • Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit based on the data presented are not possible.

b) For patients who have undergone at least one course of chemotherapy at the metastatic stage

• Consequently, given the currently limited data available, the G-BA classifies the extent of the additional benefit of avelumab as unquantifiable on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease, as non-quantifiable.
• An additional benefit exists in accordance with Section 35a(1), sentence 11, first half-sentence, of SGB V, but is non-quantifiable because the scientific evidence does not permit this.
• mortality
  • In the JAVLIN study, overall survival was defined as the time between the first administration of avelumab and death from any cause.
  • For patients who had received at least one course of chemotherapy, the median overall survival, based on data cut-off 26 September 2017, was 12.6 months (95% CI: 7.5; 17.1).
• Morbidity – Tumour response
  • In the JAVELIN study, tumour response was assessed, amongst other things, using the endpoints ‘Confirmed Best Response’ and ‘Objective Response Rate’.
  • Tumour response was assessed in accordance with the RECIST criteria. In the case of skin lesions, assessment was also carried out using colour photographs with the aid of a suitable scale.
  • The assessment of disease progression based on the RECIST criteria was therefore not symptom-based, but was carried out exclusively using imaging procedures.
  • The pharmaceutical manufacturer provided no information regarding the characteristics of the skin lesions present at the start of the study (e.g. location, extent of the lesion, degree of ulceration in patients who presented with ulceration at baseline) nor regarding changes in these lesions during treatment with avelumab (e.g. extent of the lesion or degree of ulceration). Essential information for interpreting the tumour response results is therefore lacking.
  • Overall, the tumour response endpoints in this assessment, as currently defined, are not classified as patient-relevant endpoints.
  • There is no validation of tumour response as a surrogate parameter for patient-relevant endpoints, e.g. mortality.
• Morbidity – Progression-free survival (PFS)
  • PFS was defined as the time from the start of treatment to disease progression or death from any cause, whichever occurred first. Evidence of disease progression was assessed according to the RECIST criteria.
  • With a data cut-off date of 26 September 2017, the median PFS for patients who had received at least one course of chemotherapy was 2.7 months (95% CI: 1.4; 6.9).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint had already been assessed as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of the morbidity endpoint was assessed, in accordance with the operationalisation, not on the basis of symptoms but exclusively by means of imaging procedures.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the patient relevance of the PFS endpoint. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Quality of life – FACT-M
  • Health-related quality of life was assessed using the FACT-M questionnaire. This was administered at baseline, every 6 weeks during treatment, and 28 days after the last treatment.
  • The limitations mentioned in connection with the EQ-5D VAS – namely the lack of reference to the ITT population and the analyses of patients who did not show any relevant deterioration in health status at any point after the start of treatment – apply equally to the FACT-M. Consequently, in line with the comments in the ‘Health status’ section, the results on health-related quality of life are not considered usable overall.
• Side effects
  • Adverse events occurred at least once in almost every patient as of the data cut-off date of 26 September 2017.
  • Serious adverse events (SAEs) were observed in 51.1% of patients, whilst severe adverse events (CTCAE grade ≥ 3) occurred in 71.6% of patients. AE leading to discontinuation of the study medication occurred in 9.1% of patients. Among AEs of particular interest, immune-mediated AEs were observed in 19.3% of patients and infusion-related reactions in 21.6% of patients.
• Overall assessment
  • For the benefit assessment of avelumab in the treatment of adults with metastatic Merkel cell carcinoma, results are available for patients who have received at least one course of chemotherapy at the metastatic stage, covering the endpoint categories of mortality (overall survival), morbidity, quality of life and side effects from the uncontrolled clinical study JAVELIN Merkel 200.
  • The historical data submitted by the pharmaceutical manufacturer for a naive indirect comparison in the endpoint categories of mortality and morbidity are not considered suitable for demonstrating additional benefit, particularly due to the insufficient comparability of the study populations.
  • Due to the single-arm study design and the unsuitable historical control, a comparative assessment of the study results is not possible.
  • In the present case, the decisive factor is the lack of meaningful evidence, which does not permit a valid assessment of the results.
  • Consequently, a quantitative assessment of the extent of the effect and a quantification of the additional benefit based on the data presented are not possible.

Courtesy translation only, please refer to the German original.