Early HR+/HER2- Breast Cancer

Ever since the CDK4/CDK6 inhibitor approvals have been made in advanced/metastatic HR+/HER2- breast cancer space, the companies began the race toward the early stages of the disease. But does that mean, the success rate is absolute in that area too?

Following FDA approvals, Pfizer’s Ibrance and Lilly’s Verzenio have been the key players in the metastatic HR+/HER2- breast cancer domain. With Ibrance, Pfizer had 80%-plus market share in the metastatic space whilst Lilly has not been able to make up to this level. But now the game seems to change since the companies started to investigate their respective drugs in the adjuvant setting alongside standard endocrine therapy like letrozole. The main objective of both the companies was to mitigate the recurrence of cancer, and for this, the primary outcome was decided to be invasive disease-free survival (iDFS).

Pfizer started PALLAS trial (NCT02513394), an open-label Phase III, to evaluate Ibrance for standard adjuvant endocrine therapy in pre- and postmenopausal women with Stage II or Stage III early invasive HR+/HER2 breast cancer. The company recently announced that the trial was unable to show significant improvement in the primary endpoint of invasive disease-free survival (iDFS). Since CDK4/CDK6 had shown superior data in later lines of the disease, it was anticipated that the trial would show efficacious results in early stages of breast cancer as well. Furthermore, Pfizer, in its press release, claimed that the result was disappointing, and this was not what they hoped.

While Lilly initiated MonarchE study, again a Phase III trial, wherein a total of 5,637 patients were enrolled. Further, they evaluated Verzenio combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in high risk, node-positive, early Stage III HR+/HER2- breast cancer. The company in its press release stated that the trial was able to meet the primary endpoint iDFS successfully, thereby significantly decreasing the risk of breast cancer recurrence or death compared to standard adjuvant ET alone and this result was out from a pre-planned interim analysis showing that Verzenio is the only CDK4 & 6 inhibitors to demonstrate a statistically significant reduction in the risk of cancer recurrence for people in the above segment. The company claimed that this achievement was a major milestone with the potential to change the paradigm of how early breast cancer is treated and a first for the CDK4 & 6 inhibitor class. With the satisfying data, the company is planning to speed up the innovation to people who need it and they look forward to submitting these data to regulatory authorities before the end of 2020.

Since both initiated their trials in the adjuvant setting, what nuance one can give for the failure of Ibrance and success of Verzenio?

Well, there is no apparent reason behind the failure of the PALLAS trial; however, it could be attributed to the stage of the disease.

While Pfizer enrolled either Stage 2 or Stage 3 patients with moderate to high risk of disease relapse, Lilly, on the flip side, enrolled patients with Stage 3 disease and used certain disease markers to indicate a higher risk of recurrences such as positive axillary lymph nodes, tumor-size, Bloom Richardson grading system and Ki-67 index. Pfizer claimed that if the trial had shown some efficacy, revenue would have doubled for Ibrance, which now shows that the company stock is off 6% in early trading.

With the failure of PALLAS trial, the expectations have been down for Pfizer, but the company still pins its hopes on the ongoing phase 3 Penelope-B study, investigating Ibrance in patients with a high risk of recurrence following pre-surgery chemo. The interim results are expected to be out by the end of this year. The hopes with the trial are not as much as compared to the PALLAS trial since the trial is examining a very small subpopulation within the adjuvant group.

There is one more asset in the race for the same segment, Kisqali by Novartis, wherein Novartis is running a Phase III trial called Natalee which is investigating its CDK4/6 inhibitor Kisqali in combination with endocrine therapy versus endocrine therapy alone in the adjuvant treatment of HR-positive, HER2-negative early breast cancer, with the hope of achieving the results by 2022. However, the study with a total of 4,000 patients as of now is expected to be completed by December 2025.

As Lilly expects to submit the interim results to regulatory authorities, the company will continue the MonarchE study for the analysis of final survival which is expected by 2027. As the only CDK4/6 inhibitor in the race, who knows what Kisqali has for those patients in the segment? Well, Lilly has set an emerging benchmark for the patients diagnosed with early HR+/HER2-ve breast cancer and can provide them with the outstanding results giving the pharmaceutical space a new vision of treatment.

Lilly’s success in MonarchE study and failure of Pfizer’s PALLAS trial will give the advantage to Verzenio in coming years. According to DelveInsight’s analysis, it is expected that Verzenio will lead in adjuvant settings when the drug would enter the market. Besides, it is likely that the therapy will generate approximately USD 1.5-2 billion revenue and will take the majority share.