The Costly Reality of Keytruda
Keytruda, a groundbreaking immunotherapy drug primarily used for cancer treatment, has become a significant financial strain for many patients, particularly
in low and middle-income countries like India. While its efficacy is widely recognized, the recommended fixed dosing regimen, which has evolved from an initial weight-based approach to a standardized 200mg dose every three weeks, is perceived by many Indian oncologists as unnecessarily high. This shift, implemented by the manufacturer Merck & Co. (MSD), has led to patients receiving more of the drug than medically required, thereby escalating treatment costs. Experts refer to this phenomenon as 'financial toxicity,' where the exorbitant price of such advanced therapies places them beyond the reach of a substantial portion of the patient population. The drug's journey from its initial FDA approval in 2014 for metastatic skin cancer to its current widespread use across various cancers, generating billions in revenue, highlights its importance but also underscores the accessibility challenges it presents, especially as it is not yet on India's essential medicines list and its inclusion on the WHO's model list acknowledged its unaffordability for many nations.
Rethinking Dosing Strategies
The recommended dosage for Keytruda has undergone a significant transformation since its initial approval in 2014. Initially, a weight-based dosage of 2mg/kg administered every three weeks was the standard. However, by 2016, the regimen shifted to a fixed dose of 200mg for all patients every three weeks, irrespective of their body weight. This change is particularly impactful in countries like India, where the average patient weight is considerably lower than in Western countries, meaning a fixed 200mg dose often translates to an overdose for many. Oncologists argue that this fixed dosing strategy, based on principles for chemotherapy drugs which directly kill cancer cells, is not suitable for immunotherapies. Unlike chemotherapy, immunotherapy works by stimulating the immune system to fight cancer. Dr. Atul Batra explains that once all available receptors are saturated by the drug, administering a higher dose does not increase its effectiveness, and in fact, a 'biologically effective dose' is what's crucial. Clinical trial data, including MSD's own findings, suggest that lower doses (e.g., 1mg/kg or even 3mg vs. 10mg per kg) can achieve 'complete target engagement' and demonstrate comparable efficacy to higher doses. Furthermore, the WHO expert committee has noted that weight-based dosing has been shown to maintain effectiveness while reducing costs, a practice implemented in several countries.
Evidence for Lower Doses
Emerging research and clinical observations in India provide compelling evidence that lower doses of Keytruda can be as effective as the standard high-dose regimen, while significantly reducing costs. Dr. Atul Batra led a study at AIIMS, Delhi, involving 157 women diagnosed with triple-negative breast cancer (TNBC), a particularly aggressive form of the disease. In this study, patients received either standard chemotherapy alone or chemotherapy combined with a markedly reduced dose of Keytruda – just 50mg every six weeks, which is one-eighth of the standard 200mg dose given every three weeks. The results were highly encouraging: 53.8% of patients receiving Keytruda with chemotherapy showed no signs of invasive cancer, compared to 40.5% in the chemotherapy-only group. Similarly, among those who underwent surgery, 56.7% were free of invasive cancer when treated with the lower dose Keytruda alongside chemotherapy, versus 41% with chemotherapy alone. Dr. Batra highlights that this study demonstrates the potential efficacy of a much smaller, less frequent dose, raising questions about the necessity of the higher, fixed dose. However, he points out the challenge of funding head-to-head trials comparing these low-dose and full-dose versions, a critical step for broader clinical acceptance and adoption.
Barriers to Accessible Dosing
Despite the promising evidence for lower-dose Keytruda therapy, significant obstacles hinder its widespread adoption. A primary hurdle is the manufacturer's patient assistance program, 'Kiran,' which exclusively covers the approved 200mg dose and does not recognize or support lower, potentially more affordable regimens. This effectively makes the lower dose financially impractical for many patients who rely on such programs. Compounding this issue is the drug's availability; Merck & Co. no longer markets the 50mg vial formulation, having withdrawn it for 'business reasons' in favor of the 100mg vial, as stated in a letter to the US FDA in June 2018. This move to larger vial sizes makes administering smaller, precise doses difficult and leads to unavoidable wastage. Oncologists like Dr. Amol Akhade from Mumbai's Nair Hospital criticize the company's stance, arguing that their refusal to acknowledge the efficacy of weight-based or lower doses is driven by commercial interests. If lower doses were recognized as effective, it would question the rationale behind years of fixed, high-dose recommendations. Furthermore, the 100mg vial size creates a logistical challenge for administering doses less than 100mg, especially when an open vial cannot be stored for later use, leading to further waste when smaller quantities are needed.
