Tumor-Agnostic Therapies: The Complex Path to Commercial Viability

Executive Summary

  • Tumor-agnostic treatments first came to market in 2017 with the revolutionary indication extension of KEYTRUDA® into microsatellite instability-high cancer
  • Since then we have seen two more products launch: VITRAKVI® and ROZLYTREK®. While the products gained access in the USA market, the first tumor-agnostic product to be approved in Europe, VITRAKVI®, was not granted an orphan designation and faced some payer pushback in GBR and GER
  • The current and very niche landscape of tumor-agnostic treatments focuses on small relapsed / refractory patient populations, while competing with broader-market oncology products for share which complicates commercial dynamics quite significantly
  • In order to create commercial opportunity for tumor-agnostic treatments, manufacturers will need to:
  1. Develop the oncology market to facilitate the use and reimbursement of genetic panels earlier in the treatment paradigm and drive broad awareness / education campaigns to create early genetic detection. Ultimately, physicians should be aware of the patient’s full genotype by 1L / 2L
  2. Use RWD to validate small Ph2 trial results and contextualize the benefit relative to current options, in order to achieve broad access (esp. in the EU) over the long-term
  3. Provide clear, structured, and robust data to substantiate the often-small population and ease any payer pricing concerns. Given the broad tumor application and varied SOC across tumor types, forward and HTA-specific thinking will be required to deliver clinical data that will satisfy the EU HTA bodies
  4. Follow aggressive LCM strategies to expand indicated use via targeted Ph2/3 trials to diverse tumor types
  5. Push into earlier lines of therapy with potential tumor-agnostic combination use
  6. Best positioned manufacturers for the future tumor-agnostic space are likely to have some vertical integration / partnership with the broader diagnostic process
  7. Use targeted, large epi., tumor-specific indication expansions to drive physician awareness around the product / genetic mutation and translate success on the tumor-specific side to the tumor-agnostic setting

 

CBPartners Take: Access and commercial success in the tumor-agnostic space requires manufacturers to take targeted steps beyond their existing experience in conventional oncology. However, as the market transitions to innovative clinical research designs and increased use of diagnostics, tumor-agnostic products will improve in terms of commercial potential.

Tumor-agnostic therapies target patients based on the molecular details, not tumor type – a significant movement towards a biomarker – driven paradigm

Cancer treatment has traditionally focused on the location, pathology, and size of a tumor. Molecularly-targeted therapies took the same approach at their initiation, but over the last few years, the industry saw the arrival of “tumor-agnostic” options that are used on the basis of specific biomarker expression rather than the traditional factors.

The shifting landscape of cancer treatments

For decades, surgery, radiation, and chemotherapy have been the standard of care in oncology. As our understanding of cancer biology improved, and the treatment landscape moved from blunt tools, such as cytotoxics to molecularly-targeted approaches, guidelines followed by physicians in determining optimal course of treatment for their patients and the industry’s development efforts continued to focus on the tumor tissue and staging of cancer patients (e.g., stage IV breast cancer). However, over the last few years we started to see the arrival of “tumor-agnostic” options that put tumor-site-based thinking aside and target patients on the basis of specific biomarker expression.

A closer look at the current tumor-agnostic therapies available: KEYTRUDA®, VITRAKVI®, and ROZLYTREK®

In 2017, KEYTRUDA® (pembrolizumab, $MRK), which already had numerous tumor-site specific indications, made waves in the space with the first tumor-agnostic approval from the Food and Drug Administration (FDA) for patients with microsatellite instability-high (MSI-H) cancer, or mismatch repair deficiency (dMMR). Tumors with these molecular signatures present a high mutation burden, an ideal scenario for the immune system to target and eliminate cancer cells. In investigator-initiated and company-sponsored trials KEYTRUDA® achieved response in ~40% of patients (N=149 across trials), with majority seeing durable responses over 6 months, demonstrating a strong case for this use case.

VITRAKVI® (larotrectinib, $BYR), a tyrosine kinase inhibitor of the NTRK gene, launched at the end of 2018 with a tumor-agnostic indication for solid tumors that are positive for the target gene fusion. In 2019, we also saw ROZLYTREK® (entrectinib, $RCH), another NTRK inhibitor and a direct competitor to VITRAKVI®, enter the USA market. Both drugs achieved high response rates (57%-75%) in small trials (N=54-55) and were approved through the FDA’s accelerated pathway. VITRAKVI® has also been approved by the EMA through the conditional approval mechanism.

Tumor-agnostic therapies comparison: KEYTRUDA, VITRAKVI, and ROZLYTREK

With the introduction of these agents, physicians now have a new way to target treatment for best-suited patients, even among those with more common or established tumor types. For example, some of the patients with the greatest response to VITRAKVI® were breast cancer, melanoma and colon patients. This suggests that the therapy could be a viable and competitive option for patients with these tumors, if they test positive for NTRK fusion. Furthermore, this treatment enables patients to receive the correct personalized therapy more quickly, before the cancer stages begin to advance.

If superiority vs. existing approaches are supported by additional trials, a tumor molecular signature-based approach could eventually become part of the treatment in earlier-lines. An example of the industry following this path is VITRAKVI®’s ‘basket’ clinical trial design, which is an ongoing assessment of response in both common and rarer tumor types. The NCI-MATCH trial, led by the National Institutes of Health is another substantial effort in this direction, aiming to treat patients with 11 different inhibitors based on the mutations they carry.

While the picture looks promising from a clinical perspective, there are significant uncertainties when we look at tumor-agnostic drugs from the perspective of the US and European payers.

In the USA, KEYTRUDA®’s extension into the MSI-H / dMMR tumors did not have a large impact, considering KEYTRUDA’s already established price and the small added population. The launch price of VITRAKVI®, on the other hand at USD 32,800 per month / USD 393,600 per year was perceived to be costly, especially considering its accelerated approval. The manufacturers justified the orphan-like price of the product by the small size of the target patient population (~3,000 in the USA). Months later, the competing treatment ROZLYTREK® launched at USD 17,000 per month (USD 204,000 per year), nearly 50% lower than its predecessor and more in line with the current oncology pricing trends. While the USA payers generally tend to take a hands-off approach in oncology, it will be interesting to see their response as tumor-agnostic drugs start to become available in broader groups of patients, where a number of additional options exist.

VITRAKVI® has only recently been approved by the EMA and most European authorities have not yet weighed in. However, two early opinions, a “not recommended” response from NICE in England and “no added benefit” outcome from IQWiG in GER, suggest that the path forward will be challenging. During the assessment period, VITRAKVI® is available in GER at ~EUR 16,000 per month (EUR 192,000 per year), but this price is highly likely to come down following negotiations.

The key challenges faced by tumor-agnostic therapies under development

As indicated by the initial payer response, tumor-agnostic therapies face a number of challenges in developed markets:

  • Small trial sizes and response-based assessment of clinical benefit are deemed problematic. Although response rates have been strong overall, small trial sizes with diverse sets of tumors limit the amount of data available for each tumor type expressing the relevant genetic marker. Payer and clinician stakeholders also generally expect to evaluate endpoints beyond response to ensure the drugs are providing meaningful benefit for patients. As an indicator of these concerns, both NICE and IQWiG recommended additional evidence collection, aligned with their established evidence quality requirements (e.g., comparative trial designs, use of accepted survival endpoints). While a significant hurdle in the EU, USA payers are much more forgiving of limited data availability, given the initial refractory setting, but physicians will still need convincing to opt for tumor-agnostics versus today’s more common and established tumor-specific options.

 

  • The variation of tumor types and response levels across patients in the trials may make it difficult for pathways in the USA and HTA authorites in Europe to evaluate and position these products. In the USA, the National Comprehensive Cancer Network (NCCN), as well as providers, have to determine which tumor types are the best candidates for biomarker-driven treatment. This ambiguity is particularly present for patients with common or treatable tumor types. The cross-sectional nature of tumor-agnostic data could make physicians uneasy in prescribing novel tumor-agnostic treatments, given the availability of more familiar alternatives.European HTA bodies, which have strict procedures set up to assess clinical benefit of each product in tumors defined by specific parameters (e.g., site, stage etc.) are likely to find the evidence across multiple tumors to be challenging. Separating trial data by tumor type for a traditional assessment is also not likely to support positive outcomes due to the small number of patients in each group. Drugs with orphan designations from the EMA can generally overcome some of these requirements, but the EMA’s current rules need to be adjusted for tumor-agnostic therapies to realize this benefit.

 

  • Biomarker-specific pathways and guidelines will likely take a significant amount of time to take shape given the delay in data collection. Building new modalities into these algorithms is expected in the future, but far more data are required as well as more therapeutic options to treat biomarkers, before stakeholders can be assured of the value of these types of approaches. Until then, tumor-agnostic therapies will predominantly remain buried within existing tumor-specific guidelines, only reachable after multiple established therapeutic steps. In parallel, the physician approach to treatment will also need to evolve to test patients for specific genetic markers and treat with the tumor agnostic options, while the established therapies, such as PDx’s, are available much faster. Manufacturers need to be ready for a significant amount of market shaping in terms of guidelines, payer and physician perspectives as well as a long-term perspective (investment) on the tumor-agnostic modality.

 

  • Finally, appropriate use of targeted treatments is only possible through robust molecular testing of tumors. While several technologies exist and new ones are in development, the process is not one-size-fits-all, and testing for all possible mutations is still costly. Furthermore, detection of certain genetic signatures requires specific testing methodologies, which requires development of additional tests and their acceptance by the clinical community. Best positioned manufacturers for the future tumor-agnostic space are likely to have some vertical integration / partnership with the broader diagnostic process.

 

Diagnostic testing is a hurdle that could have implications for access to tumor-agnostic therapies

The top eight commercial considerations for tumor-agnostic therapies

Considerations for success with tumor-agnostic therapies

 

Recommendations for manufacturers looking to launch tumor-agnostic therapies

The tumor-agnostic space is incredibly exciting and an area that is likely to be explored further. To realize the benefits of these new therapies and facilitate patient access to tumor-agnostic therapies, manufacturers will need to take several actions to ensure uptake and encourage ongoing innovation in the relevant cancers.

Before tumor-agnostic products may be considered as a serious treatment option for oncology patients, manufacturers will need to continue with robust research and development, educating stakeholders, and building confidence among providers.

Additional evidence generation is also critical from a European access perspective. In the foreseeable future, most HTA bodies are still likely to demand an evidence package supporting clinical benefit compared to the standard of care within each tumor type. In order to respond to these demands, the manufacturers should consider well-designed randomized controlled trials (RCTs). In some markets, real-world evidence collected through different mechanisms and synthetic comparator arms can also be leveraged to alleviate some payer concerns.

As commercial success will be more difficult than the conventional oncology process it also means the payoff is likely to be delayed. Aggressive lifestyle management programs and market shaping have the potential to make these therapies strong oncology assets, which will have a profound impact on their manufacturers’ positions in the market, particularly as innovation leaders.

The tumor-agnostic treatment therapeutic approach is likely to become more prevalent as new targetable biomarkers that play similar roles across a wide range of tumors are identified, and pursuing investment in research and development for tumor-agnostic indications will ultimately be worthwhile for manufacturers. These opportunities will arise sooner if the industry continues to lay the groundwork of genetic-testing, NGS availability, robust clinical and real-world evidence development, and published data.

Authors