Drug Targeting Offers Hope for Patients with Non-Small Cell Lung Cancer that Harbors Rare Mutations

After Robin Kwiecien was diagnosed with non-small cell lung cancer (NSCLC) in 2018, she started a course of targeted radiation, which kept the disease under control for nearly two years. When the cancer progressed in late 2019, a biopsy revealed that the tumors had an “activating” genetic mutation called KRAS G12C — making Kwiecien eligible for a clinical trial of a drug targeting that exact abnormality.

Kwiecien, 66, a retired pharmacy technician in Duluth, Georgia, was accepted into the trial in February and put on a dosage of eight tablets per day of the experimental oral drug sotorasib. After six weeks on a daily dose of sotorasib, Kwiecien got some good news: The tumors had shrunk by 22%. She didn’t need to undergo chemotherapy or take any other drugs during the trial. So aside from a little shortness of breath caused by the cancer, she says, “I’m not showing any major symptoms. I haven’t felt bad in any way, shape or form.”

Oncologists have long been aware of “driver” mutations in genes — abnormalities that can cause the onset and growth of cancer. KRAS and EGFR are examples of genes that can become mutated and drive lung tumors and several other cancers. But in recent years, oncology researchers have discovered subsets of these mutations that some refer to as “superdrivers” because they can cause cancer growth on their own, seemingly without the dependence on other tumor mutations.

KRAS G12C and EGFR exon 20 insertions are super- driver mutations that can make NSCLC particularly difficult to treat. About 12% of patients with NSCLC have the KRAS G12C mutation. EGFR mutations are quite common in NSCLC, with a prevalence of about 32% in a recent analysis of records from more than 115,000 patients worldwide. Exon 20 insertions account for 4% to 10% of those EGFR-positive cases.

Patients with KRAS G12C and EGFR exon 20 insertions typically don’t respond well to chemotherapy and other established treatments, including drugs that were approved by the Food and Drug Administration to target other

EGFR mutations. The good news is that drugs developed to address these less common mutations are progressing through clinical trials — and offering the prospect that targeted treatments will improve the prognosis for patients in the future.

“This reflects the evolution of lung cancer therapy. We’re dividing lung cancer into smaller subgroups and then developing more specific therapies for each of them,” says Dr. John Heymach, chair of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. “It’s an exciting time.”

Cracking A Challenging Mutation

The KRAS gene belongs to a class of genes that, when mutated, are known to cause normal cells to become cancerous. KRAS encodes proteins that are involved in normal cell signaling, but mutations can cause those signals to become sustained, resulting in uncontrolled cancer growth. KRAS mutations can also make some cancer cells resistant to chemotherapy. But targeting KRAS with drugs has proven challenging.

There are several subtypes of KRAS mutations, including G12D and G12V, but KRAS G12C is of particular interest in lung cancer because of its prevalence. Sotorasib, the most advanced drug in the pipeline targeting KRAS G12C, is designed to lock the mutated cancer-associated protein into an inactive state “so it no longer signals and no longer drives cancer growth,” explains Dr. Greg Durm, assistant professor of clinical medicine at Indiana University School of Medicine and one of the investigators for the sotorasib trial.

In September, data from an early trial of sotorasib was released showing that 32% of patients with NSCLC who participated responded to the drug and that the overall rate of disease control was 88%. Phase 2 trial results announced in October confirmed those findings.

A second KRAS G12C inhibitor, MRTX849, also looks promising in NSCLC. Six patients with NSCLC received the drug in a study released in October 2019, and three of them had a partial response.

The drugs also seem to be well tolerated, with few serious side effects reported in the trials so far. “Many of the patients we’ve had (on sotorasib) tell me they feel as well on this drug as they have in some time,” Durm says. “That’s because many of them have been on chemotherapy, with side effects like fatigue, vomiting and rashes. Most of that resolves on this drug when it’s given alone.”

Even though KRAS G12C inhibitors are still in early testing as solo therapies, oncologists and drug developers are already thinking about their potential as part of combination strategies. Sotorasib is being tested along with the chemotherapy drug docetaxel, for example, as well as in combination with Keytruda (pembrolizumab), an immunotherapy drug that blocks the checkpoint protein PD-1.

“These combination approaches are based on biological evidence that targeting multiple pathways related to KRAS could result in additive benefit,” says Dr. Suresh Ramalingam, deputy director of Winship Cancer Institute of Emory University and a professor of hematology and medical oncology at the Emory University School of Medicine in Atlanta and one of the investigators for the sotorasib trials.

Targeting EGFR Mutation Subtypes

Evelyn Saunders Webb had part of her right lung removed while being treated for NSCLC in 2014. That’s when her doctors at MD Anderson Cancer Center discovered her cancer had the EGFR exon 20 insertion mutation. Four years later, after chemotherapy and radiation helped tamp down two recurrences of the disease, Webb was accepted into a trial of an experimental oral drug called poziotinib.

Shortly after Webb was first administered poziotinib, her cancer regressed by 50%. Her disease has been stable ever since. Aside from occasional digestive issues and a rash that she controls with an antibiotic, Webb hasn’t noticed any symptoms from either the drug or the cancer. “I feel good,” says Webb, 74, who lives in San Antonio. “I walk two to three miles a day and do everything I would normally do.”

Heymach says that EGFR-targeted drugs such as Tarceva (erlotinib) and Gilotrif (afatinib) are often effective in patients with the most common EGFR mutations: exon 19 deletions and L858R. “But about 20% of patients have what we call atypical EGFR mutations, and the biggest group have exon 20 insertions,” he says.

EGFR exon 20 insertion has been challenging to target, in part because the mutated version of the gene looks similar to normal EGFR, which is involved in the growth and differentiation of healthy cells in the body. “So, the trick has been to develop drugs that inhibit the mutation but leave normal EGFR alone,” Heymach says.

Poziotinib is currently in phase 2 trials in patients with NSCLC harboring EGFR exon 20 insertion mutations. Data released in September from one trial showed that 63 out of 90 patients who received the drug achieved disease stabilization and 67 had tumor shrinkage. Studies from Heymach’s group at MD Anderson have shown response rates of 30% to 40%.

“Our best EGFR inhibitors for classical mutations work in 60% to 70% of patients, but none of those drugs work for exon 20 insertion mutations,” Heymach says.

“So (poziotinib) isn’t quite as good (as EGFR inhibitors are in treating classical mutations), but it’s much better than nothing.”

The side effects of the drug, primarily rash and diarrhea, were difficult for Webb at first, but they became manageable after she was switched to a lower dose of poziotinib. She still watches what she eats — for example, the spicy Mexican food that’s so popular in Texas is off-limits — and she has to stay out of the sun as much as possible. But it’s worth it, she says: “The payoff is my cancer isn’t growing.”

Mobocertinib, another drug being developed for patients with the EGFR exon 20 insertion mutation, received breakthrough designation from the FDA in April and will get an expedited review, based on data showing an overall response rate (including all partial and complete responses) of 43% in patients participating in an early trial. The drug is now being tested in a phase 3 trial comparing it with chemotherapy in newly diagnosed patients.

Another drug for exon 20 insertion mutations that received an FDA breakthrough designation is amivantamab, which is referred to as a “bispecific antibody” because it has two modes of action. One arm targets EGFR and the other targets MET, another gene that can drive EGFR-mutated cancers. The drug is also designed to direct the body’s own cancer-killing immune cells to tumors. In an early trial, 41% of patients who had previously been treated with chemotherapy responded to amivantamab.

Amivantamab is now being studied in a phase 3 trial in combination with two chemotherapy drugs. Oncologists are also interested in exploring other combination strate- gies for treating patients with EGFR exon 20 mutations, but in this case, those combinations are unlikely to include immunotherapy, says Dr. Pasi Jänne, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston. “Lung cancer patients who have EGFR mutations don’t really benefit from immunotherapy, and there is clearly more toxicity when you add checkpoint inhibitors to an EGFR inhibitor,” he says.

Exploring Early Treatment With Targeted Drugs

Several drugs being tested for EGFR exon 20 insertions are also being studied in patients with human epidermal growth factor receptor 2 (HER2) gene mutations. HER2 is a member of the same family as EGFR, and the mutation is so structurally similar to the EGFR exon 20 insertion that “if you make a drug against one, it will most likely inhibit the other,” Jänne says. About 4% of patients with NSCLC have HER2-mutated tumors.

In a small trial of poziotinib in HER2-positive NSCLC, approximately 50% of patients responded, and more extensive data in this subset of patients is expected soon for some of the other drugs originally designed to target EGFR exon 20 insertion mutations.

One drug that was FDA approved to treat HER2-positive breast cancer, Enhertu (fam- trastuzumab deruxtecan-nxki), is showing promise in HER2-positive NSCLC. In an ongoing phase 2 trial, 90% of patients treated with Enhertu saw the disease improve or stay stable, and 62% of patients had tumors partially or completely respond. All patients in the trial had received at least one prior therapy.

KRAS G12C, HER2 and EGFR exon 20 inser- tion mutations can be detected with DNA, or “biomarker,” testing of tumor samples collected during biopsies. Some insurance companies may not cover all available tests, so patients should talk with their oncologists about both the logistics and costs of comprehensive biomarker testing.

The early promise of drugs addressing KRAS G12C and EGFR exon 20 insertion mutations has raised interest in studies designed to determine whether they should be used earlier in the treatment process — before chemotherapy or other targeted drugs.

“These are mutations that happen early on and are in every single part of the cancer,” says Dr. Joel Neal, associate professor of medicine at Stanford University Medical Center in California and one of the investigators for the mobocertinib trial. “That makes them powerful to target because if you can turn off the proteins that result from these mutations, you can kill a lot of the cancer cells or make them not divide.”

Six months after entering the trial of sotorasib, Kwiecien learned that the tumors stopped shrinking. But she isn’t discouraged, she says. In fact, she’s so optimistic that scientific advances will improve the chances for patients in the future that she’s already looking for another clinical trial.

“I didn’t go into a clinical trial with an expectation of a cure,” Kwiecien says. “I wanted to somehow give back in some small way through research. I would like to continue to do that.”

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