Treatment Updates

At the start of 2020, there are more than 500 Phase III precision medicine trials slated for completion over the next two years, primarily for various biomarker-defined cancer indications. If only 20 percent of these studies are successful, it is projected that drugmakers may submit around 100 new drug or biologic license applications to the FDA in the coming years.

In May, the FDA approved olaparib (AstraZeneca/Merck's Lynparza) for men with metastatic castration-resistant prostate cancer who had mutations in 15 genes involved in homologous recombination repair as defined by Myriad Genetics' BRACAnalysis CDx and Foundation Medicine's FoundationOne CDx. Earlier that same month, the agency had approved olaparib and bevacizumab (Genentech's Avastin) as first-line maintenance therapy for advanced ovarian cancer patients responsive to platinum chemotherapy, who have homologous recombination repair deficiency. But the biomarker in the ovarian cancer indication is defined differently than in the prostate cancer setting and is determined by Myriad's myChoice CDx.

In the first six months of 2020, the FDA approved seven new molecular entities (NMEs) and expanded the use of 14 already approved drugs into new molecularly defined indications for a total of 21 precision oncology drugs. The agency approved new companion tests (CDx) alongside 10 drugs, but allowed several new drugs for rare molecularly defined indications to come to market without a specific CDx, such as Retevmo (Eli Lilly's selpercatinib) for lung and thyroid cancers with RET mutations and fusions. Such drugs will rely on already available tests on the market to identify best responders. these recently approved drugs rely on a mix of new biomarkers like homologous recombination repair deficiency and tumor mutational burden (TMB), and established biomarkers like HER2 expression. For example, the FDA approved a new drug combination, neratinib (Puma Biotechnology's Nerlynx) with capecitabine, for advanced HER2-positive breast cancer patients who are refractory to other HER2-targeted drugs.

In all, the FDA has now approved four tissue-agnostic indications, and two of them have been for pembrolizumab, first using microsatellite instability and mismatch repair status, and now, relying on TMB to predict which cancer patients with refractory solid tumors might respond.

Immunotherapy Treatment Updates

During August 1, 2018 to July 31, 2019, the FDA approved one checkpoint inhibitor for the first time—cemiplimab-rwlc (Libtayo)—and expanded the uses of four of the previously approved checkpoint inhibitors—avelumab (Bavencio), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda)—to include the treatment of additional types of cancer. As of July 31, 2019, there was at least one checkpoint inhibitor approved for treating 15 types of cancer and for treating any type of solid tumor characterized by the presence of specific molecular characteristics.

Cemiplimab-rwlc became the seventh checkpoint inhibitor approved by the FDA in September 2018. It was approved for treating patients who have metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma that cannot be treated with curative surgery or curative radiation. The approval was based on results from two small clinical trials. Overall, 47 percent of the patients who received cemiplimabrwlc had complete or partial tumor shrinkage.

March 2019 marked another milestone in the era of checkpoint inhibitors. The FDA approved expanding the use of atezolizumab to include treating adults who have metastatic triple-negative breast cancer that tests positive for PD-L1 protein and adults who have locally advanced triple-negative breast cancer that cannot be removed by surgery and tests positive for PD-L1 protein. The approval was for the use of the checkpoint inhibitor in combination with the cytotoxic chemotherapeutic nab-paclitaxel (Abraxane). At the same time, the FDA approved the Ventana PD-L1 Assay as a companion diagnostic to identify patients with PD-L1–positive, triple-negative breast cancer.

Triple-negative breast cancer accounts for about 12 percent of breast cancer cases diagnosed in the United States each year. Breast cancers are classified as triple-negative if they test negative for hormone receptors and the protein HER2. Until the approval of atezolizumab, cytotoxic chemotherapeutics were the only systemic treatment options for patients with triple-negative breast cancer.

Atezolizumab was approved for treating an additional type of cancer in March 2019. It was approved for use in combination with two cytotoxic chemotherapeutics, carboplatin and etoposide, for the initial treatment of adults diagnosed with extensive-stage small-cell lung cancer (SCLC). The FDA approved expanding the use of both nivolumab and pembrolizumab to include treating patients who have extensive-stage SCLC that has progressed despite treatment with a platinum-based cytotoxic chemotherapeutic and at least one other cytotoxic chemotherapeutic. SCLC accounts for about 15 percent of lung cancers diagnosed each year in the United States. Most patients are diagnosed with extensive-stage disease, which means the cancer has spread beyond the lung, or the area between the lungs or the lymph nodes above the collarbone to other parts of the body.

In November 2018, pembrolizumab was approved by the FDA for treating patients who have hepatocellular carcinoma that has progressed despite treatment with the molecularly targeted therapeutic sorafenib, which has been the standard of care for patients with this disease for more than a decade. The approval was based on results from a phase II clinical trial that showed that treatment with pembrolizumab led to partial or complete tumor shrinkage in 17 percent of patients. Most of these patients benefited from pembrolizumab treatment for 12 or more months.

The other new FDA approval for pembrolizumab occurred in April 2019. The checkpoint inhibitor was approved for use in combination with the molecularly targeted therapeutic axitinib (Inlyta) for the initial treatment of patients who have advanced renal cell carcinoma, which is the most common type of kidney cancer. The combination of pembrolizumab and axitinib was approved after results from a phase III clinical trial showed that the combination significantly improved overall survival rates compared with sunitinib (Sutent), which is one of the most commonly used initial treatments for patients newly diagnosed with advanced renal cell carcinoma.

Lung Cancer Targeted Treatment Updates

One of the genes most frequently mutated in NSCLC cancer is EGFR. Dacomitinib (Vizimpro) is a new EGFR-targeted therapeutic approved by the FDA in September 2018. It was approved as an initial treatment for patients with metastatic NSCLC that tests positive for certain EGFR mutations, either an EGFR exon 19 deletion or the exon 21 L858R mutation. The approval was based on results from a phase III clinical trial that showed that treatment with dacomitinib significantly increased the time to disease progression compared with gefitinib (Iressa), which is the EGFR-targeted therapeutic most commonly used to initially treat patients with metastatic NSCLC that tests positive for EGFR mutations. Such second-line treatments are important because many NSCLCs that initially respond to molecularly targeted therapeutics eventually progress due to the development of treatment resistance.

In November 2018, the FDA approved a molecularly targeted therapeutic called lorlatinib (Lorbrena), providing a new option to help patients with NSCLC fueled by mutations in the ALK gene to address the challenge of treatment resistance. The ALK gene is another gene frequently altered in NSCLC. Research has shown that the secondgeneration ALK-targeted therapeutics—ceritinib, alectinib, and brigatinib—can inhibit most of the ALK mutations that drive resistance to crizotinib and the third-generation ALK-targeted therapeutic—lorlatinib—can inhibit most of the ALK mutations that drive resistance to the second-generation ALK-targeted therapeutics. The approval was based on results from a phase II clinical trial that showed that 48 percent of patients with ALK mutation–positive metastatic NSCLC who had previously been treated with one or more ALK-targeted therapeutics had complete or partial tumor shrinkage following treatment with lorlatinib.

Breast Cancer Targeted Treatment Updates

For patients with breast cancer, one factor determining what treatment options should be considered is the presence or absence of three tumor biomarkers, two hormone receptors and HER2. About 70 percent of breast cancers diagnosed in the United States are characterized as hormone receptor–positive and HER2-negative. Potential treatment options for these patients include therapeutics such as tamoxifen, which works by preventing the hormone estrogen from attaching to its receptor; letrozole, which works by lowering the level of estrogen in the body; and fulvestrant, which works by reducing the number of receptors for estrogen to bind to and by preventing estrogen from attaching to its receptor. Treatment with these therapeutics is often called endocrine therapy.

Unfortunately, most advanced, hormone receptor–positive breast cancers that initially respond to endocrine therapy eventually progress because they have become treatment resistant. In May 2019, the FDA approved the molecularly targeted therapeutic alpelisib (Piqray) as a new treatment option to help address this challenge. Alpelisib was approved by the FDA for use in combination with fulvestrant for treating men and postmenopausal women who have advanced or metastatic, hormone receptor–positive, HER2-negative breast cancer that tests positive for PIK3CA mutations and has progressed during or after endocrine therapy. This approval was based on results from a phase III clinical trial that showed that adding alpelisib to fulvestrant almost doubled the time before disease progression. At the same time that the FDA made the decision about alpelisib, it approved the therascreen PIK3CA RGQ PCR Kit as a companion diagnostic to test patients for PIK3CA mutations.

Another FDA decision that provided an advance against breast cancer was the October 2018 approval of the molecularly targeted therapeutic talazoparib (Talzenna) for treating patients with metastatic or locally advanced, HER2-negative breast cancer who have inherited a known or suspected cancer-associated BRCA1 or BRCA2 mutation. At the same time, the FDA approved using the BRACAnalysis CDx test as a companion diagnostic to identify patients who are eligible for talazoparib. About 5 percent of all breast cancers diagnosed in the United States are attributable to an inherited BRCA1 or BRCA2 mutation. The approval of talazoparib was based on results from a phase III clinical trial that showed that treatment with the molecularly targeted therapeutic significantly increased the time to disease progression compared with treatment with a cytotoxic chemotherapeutic.

Given the benefits of talazoparib and another PARP inhibitor called olaparib (Lynparza) for patients with metastatic or locally advanced, HER2-negative breast cancer who have inherited a known or suspected cancer-associated BRCA1 or BRCA2 mutation, patients should talk with their health care providers about whether they are at high risk for having inherited one of these mutations and whether genetic testing is right for them. This is important because a recent study found that half of patients with breast cancer who were at high risk for having inherited a known or suspected cancer-associated BRCA1 or BRCA2 mutation had not had a genetic test.

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