2020-06-03| R&D

ASCO 2020: Keytruda Chemo Combo Show Significant Benefit in PD-L1 Expressing mTNBC

by Sangeeta Chakraborty
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By Sangeeta Chakraborty, Ph.D.

Breast cancer (BC) is one of the most common forms of cancers diagnosed among women worldwide and is the second leading cause of mortality in women after lung cancer. As per US breast cancer statistics, about 1 in 8 US women will develop invasive breast cancer in her lifetime, while 276,000 estimated cases of invasive breast cancer are expected to be diagnosed in women in 2020. Although significant declines in BC related mortality have been achieved over the past three decades (through 2017), owing to early detection and treatment of the disease, BC incidences have been slowly rising since then.


Triple-Negative Breast Cancer (TNBC)

Accounting for almost 10-20% of all breast cancers, TNBC is mainly an aggressive subtype with higher-grade pathology and a poor prognosis. It lacks estrogen receptor, progesterone receptor, and amplification/overexpression of human epidermal growth factor receptor (HER2), which are present on the malignant cells from other subtypes of breast cancer. As a result, TNBC is unresponsive to traditional hormone therapy or HER2-targeted therapy, making it more challenging to treat. Currently, treatment options include surgery, radiation therapy, and chemotherapy, depending on the degree of invasiveness and spread of the tumor cells. Researchers are continually working to find new regimens that can increase long-term disease-free survival for patients with TNBC, which has a high recurrence rate within the first five years following diagnosis.


Keytruda’s Advance in Treating metastatic TNBC (mTNBC)

Keytruda (pembrolizumab), the miracle ICI drug from Merck and Co, has been making a lot of buzz in cancer immunotherapy and for the right reasons; presently the drug is indicated for the treatment of a variety of cancers including, but not limited to, drug-resistant melanoma, head and neck cancers, non-small cell lung cancer, metastatic bladder cancer, and Hodgkin’s lymphoma. It is currently being evaluated in close to 400 clinical trials covering numerous other solid and blood tumor types.

Based on the results from the phase 1b KEYNOTE-173 and phase 2 I-SPY2 trials, Keytruda plus chemotherapy was granted breakthrough therapy designation by the FDA to treat high-risk, early-stage TNBC in the neoadjuvant setting.

Later on, in the KEYNOTE-522 trial, this combination achieved higher rates of pathological complete response (pCR; no active cancer cells present in resected tissue samples from surgery) and positive trend for event-free survival as compared to chemotherapy alone, in a neoadjuvant setting for treatment of early-stage TNBC.



KEYNOTE-355—a two-part study—tested the efficacy and safety of Keytruda in combination with chemotherapy as a first-line treatment for locally recurrent inoperable or metastatic TNBC, which has not been previously treated with chemotherapy.

Part 1 of the clinical trial evaluated the toxicity profile of Keytruda plus three prescribed chemotherapy regimens in a handful of 30 patients, according to the following treatment regimen.

  1. Keytruda (day 1; 21-day cycle) + nab-paclitaxel (day1, 8, and 15; 28-day cycle)
  2. Keytruda (day1; 21-day cycle) + paclitaxel (day1, 8, and 15; 28-day cycle)
  3. Keytruda (day1; 21-day cycle) + gemcitabine/carboplatin (day1, and 8; 21-day cycle)

Part 2 of the study, which evaluated the safety and efficacy of the drug, enrolled 847 patients who were randomized to receive either the same above treatment regimen or placebo with chemotherapy drugs. The dual primary endpoints of the study are:

  1. progression-free survival (PFS) and
  2. overall survival (OS)

in TNBC patients with PD-L1 positive tumors, measured as a combined positive score (CPS). [Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100]. Patients were further sub-grouped into those with CPS≥1, CPS≥10, and an overall intention to treat (ITT) population.

Secondary endpoints of the trial include objective response rate, duration of response, disease control rate, and safety.

One of the primary endpoints (PFS) results were discussed in the 2020 ASCO virtual meeting. The combo treatment registered a superior PFS across all patient subgroups, which was especially pronounced and statistically significant in patients with PD-L1 enrichment (CPS≥10).

In the CPS≥10 sub-group, 61.8% of patients experienced disease recurrence compared with 76.7% in the placebo arm. In fact, an impressive hazard ratio of 0.65 (35% reduced chances of disease recurrence) was registered with the combo therapy. The median duration of time for which patients remained disease-free after the neoadjuvant treatment was longer (9.7 months) with the combo therapy than the placebo arm (5.6 months).

In the CPS≥1 sub-group, however, Keytruda with chemotherapy showed only a modest advantage in slowing down cancer recurrence over the placebo arm (67.8% vs. 76.8%). Even though the median PFS was higher (7.6 months) with the combo therapy than with the placebo arm (5.6 months), it did not pass statistical significance.

The benefit of Keytruda as combinatorial therapy in improving PFS in both CPS≥10 and CPS≥1 patients was consistent across all subgroups, including age, geographic region, prior chemotherapy status.

Although the safety profile of Keytruda plus chemotherapy did not result in pronounced adverse effects and was consistent with the known profiles of each chemotherapy drug, immune-related side effects mostly endocrinopathies, including hypo and hyperthyroidism and pneumonitis, occurred at a higher rate (25.6% vs. 6% in placebo); however, these did not result in any death.

Triple-negative breast cancer is an aggressive malignancy. It is encouraging that the Keytruda chemo combo has now demonstrated positive results as both a first-line treatment in the metastatic setting with this trial and as neoadjuvant therapy in the KEYNOTE-522 trial, said Roger M. Perlmutter, MD, Ph.D., President, Merck Research Laboratories, in a statement.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: ASCO 2020: Immunotherapy Gives Hope to Women with Placental Cancer



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