Written by Danny Cohen And Scott Matusow
This past weekend at The Society for Immunotherapy of Cancer (SITC) Calithera Biosciences Inc (NASDAQ:CALA) presented a first interim look into their multi-cohort Nivolumab and CB-839 combination study in solid tumors. The study looked at 3 tumor types: Non-small cell lung cancer (NSCLC), Melanoma (MEL), and Renal Cell Carcinoma (RCC). Three of the cohorts involved each of the former tumor settings in PD-1 rescue, where 839 was cycled onto active progressors determine if the patients could stabilize and respond. The two other cohorts were also in RCC with one for IO naive and other for any prior IO line. While the interim data on surface may seem less than impressive, we feel that there is more than meets the eye here with Calithera and its progress being made to better identify patients likely to respond to glutaminase inhibition.
The biomarker panel revealed at SITC regarding the MEL patients (3 clinical responses) shows that 839+PD-1 cannot completely re-heat a ‘cold’ tumor when immune markers are severely blunted for heavily-refracted patients.
However, ‘warm’ signature tumors can be turned ‘hotter’ in order to generate a response. One factor that should be considered in reviewing this early data, is that all the MEL patients were relapsed following IO treatment, and therefore, it’s highly likely that these patients had significant immune exhaustion. Increasing glutamine availability to T-cells and restoring function may take longer due to this exhaustion Further review of this factor should offer insight as to how to prioritize treatments for maximize response.
One possibility is to look at an induction treatment (with a combination) to heat up the tumor from a cold to a warm state, such as a chemo/839 combination like we saw in triple-negative breast cancer (TNBC). Perhaps overlooked by the market, was that the company posted an updated abstract on The San Antonio Breast Cancer Symposium (SABCS) website revealing that the responses from last year continue to be durable in African-Americans with a 36% ORR and 55% DCR as of May.
Similar to the PD-1 study, the use of 839 was designed to salvage a failed taxane-based therapy . Interestingly, it’s been shown that following taxane administration, TNBC cell lines rather than Luminal A lines (ER and/or PR positive) responded by up-regulating glutamine metabolism as a resistance mechanism.
When looking at TNBC, we see that these tumor types are characterized by significant metabolic differences such as increased 2-hydroxyglutarate (2HG) levels, which are a marker of glutaminase expression. This 2HG expression is also matched with MYC, a commonly expressed pathway in cancer, and increased methylation on the patient DNA.
The study correlated all these notable markers directly to a subtype defined by methylation subgroup III, with a significantly disproportionate African-American population. Notably, patient-wide studies have revealed that TNBC patients that have high expression of glutaminase also tend to have a relatively low level of tumor-infiltrating lymphocytes (TILs), which is characteristic of the “cold” tumor phenotype. This glutaminase expression is typically further characterized with a significantly worse prognosis. Lastly, African American patients are much more likely to have TNBC over other breast cancer types. The question needs to be asked, “Is there a genetically defined bridge between African-American women, loss of hormone receptors which defines TNBC, the cold tumor phenotype and glutamine utilization?”
Taken together, it’s evident that African Americans not only have a tendency towards TNBC, but that there are distinct markers defining metabolic alterations that can sensitize a patient using CB-839. It can be hypothesized that in such patient populations defined by glutamine dependency, the cold phenotype can be turned warm using a chemotherapy combination.
The restoration TIL expression further enables a follow-on therapy with PD-1 to ensure a durable or an even deeper response as the tumor turns from warm to hot. Many other therapy options for TNBC would also become available following such a pre-treatment – even outside of the difficult IO space. For example, a combination with mTOR could potentially block both metabolic pathways in a tumor following an initial reduction in mass. This would starve the tumor, (which is already in a stressed state) and would be far more immunogenic. This could lead to a deeper or even complete response over time. Interestingly, Sanofi appears to have examined such a combination of 839 and mTOR in TNBC in an IND enabling study published earlier this year. Strangely enough, this study dates back roughly 4 years ago, prior to the Calithera IPO. We wonder why Sanofi would submit older paper to be published in late September in an open access forum? What exactly is Sanofi’s interest in Calithera’s 839? Is Sanofi interested in a chemo/839/mTOR triplet combo?
We think it is important to note that Calithera’s biomarker work to define an optimal treatment design is markedly distinct from the data that Nektar Therapeutics presented over the weekend. While Nektar’s data showed impressive responses, it’s important to recognize that this work was done in an early line setting where patients did not have an exhausted immune phenotype as we saw with Calithera’s patient population. Many of the comparisons between the two sets of data that we have seen from the investment community are unfounded and show a lack of understanding for the rapidly evolving IO space – basically akin to comparing apples with oranges so-to-speak.
In conclusion, it will be important to follow these potential developments into the clinic, and how Calithera explores the TNBC program. We are especially interested in TNBC in relation to African-Americans, as African-American women are 3 times more likely than white or Hispanic women to be diagnosed with triple-negative breast cancer. As previously mentioned, African-America woman showed a durable and outstanding ORR in the May 2017 results.
Disclosure: We are long CALA.
We wrote this article ourselves, and it expresses our own opinions. We are not receiving compensation for it. We have no business relationship with any company whose stock is mentioned in this article.