Non–Small Cell Lung Cancer Coverage from Every Angle


Posted: Tuesday, March 22, 2022

In May 2021, the U.S. Food and Drug Administration (FDA) approved the first oral targeted therapy for patients with non–small cell lung cancer (NSCLC) whose tumors harbor a specific KRAS mutation called KRAS p.G12C.1 Currently, sotorasib is indicated2 for patients with locally advanced or metastatic NSCLC after disease progression on a first-line regimen such as platinum-based chemotherapy and/or an immune checkpoint inhibitor.

Approval was based on results from the phase II NSCLC cohort of the CodeBreaK 100 trial.3,4 This study focused on 126 patients with KRAS p.G12C–mutated advanced NSCLC who had previously been treated with at least one and up to three prior lines of systemic therapy including chemotherapy, immunotherapy, or combinations. A confirmed objective response was observed in 37.1% of patients, with 3.2% exhibiting a complete response and 33.9%, a partial response to therapy. Disease control (tumors shrunk or remained stable) was observed in 80.6%, and median overall survival was 12.5 months. The median duration of response was 11.1 months, and median progression-free survival was 6.8 months.

The addition of sotorasib to the treatment arsenal for patients with lung cancer is particularly welcome because although KRAS is recognized as a significant driver of many adenocarcinomas, it had been heretofore considered a resistant or “undruggable” target.

Role of the RAS Oncogene in the Development of Lung Adenocarcinomas

Asked about the size of the population of patients with lung cancer for whom sotorasib might be appropriate, Ferdinandos Skoulidis, MD, PhD, Associate Professor with the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, explained: “Mutations in KRAS represent the most prevalent oncogenic driver in nonsquamous NSCLC and are identified in approximately 25% to 30% of [adenocarcinoma] tumors.” The KRAS p.G12C mutation is the most common KRAS alteration in NSCLC and is identified in roughly one in eight patients with nonsquamous NSCLC.5,6 “This is a fairly large group of patients for whom there had been no targeted therapy until very recently,” Dr. Skoulidis told JNCCN 360.

Mutations in KRAS represent the most prevalent oncogenic driver in nonsquamous NSCLC and are identified in approximately 25% to 30% of [adenocarcinoma] tumors.

KRAS as an Oncogenic Driver

The most common KRAS mutations involve substitutions of glycine at position 12, Dr. Skoulidis explained. These substitutions impair the stimulation of GTP hydrolysis by GTPase activating proteins.7 The effect is that KRAS is “rendered constitutively active and is therefore able to continuously and inappropriately engage with downstream effectors that mediate diverse hallmarks of cancer, such as unscheduled cellular proliferation, evasion of apoptosis, invasion, and metastasis.”

An ‘Undruggable’ Target?

Despite knowing that KRAS has been a major driver of adenocarcinoma development, there has been little progress in efforts to directly target KRAS.8-10 There are several well-documented reasons for this, Dr. Skoulidis observed. First, the affinity of KRAS for its substrate, GTP, is in the picomolar range. “This, coupled with the high intracellular concentration of GTP, makes the development of competitive inhibitors of KRAS extremely difficult,” he said.

The second reason has to do with the structure of the KRAS oncoprotein,11,12 which may be “visualized as a smooth and relatively featureless ball with few hinges or crevices to which a small molecule could attach.” The third reason is that KRAS is critical for the function of normal cells. “A successful inhibitor with an acceptable therapeutic window would therefore have to be selective for mutant KRAS and spare wild-type KRAS,” he continued. Finally, compared with other oncogenically driven subtypes of NSCLC, such as those fueled by EGFR activating mutations or ALK rearrangements, KRAS-mutant lung cancers tend to be biologically diverse and clinically heterogeneous.13

“One patient’s KRAS-mutant NSCLC can behave differently from another’s,” Dr. Skoulidis explained. That may have to do, at least in part, with the fact that many patients with KRAS-mutant NSCLC have significant exposure to tobacco, he noted; as such, their tumors frequently harbor a high number of additional mutations in diverse oncogenic drivers.

Co-occurring Mutations in NSCLC

We know that co-occurring genomic alterations6 (ie, mutations in genes other than KRAS itself) can profoundly shape the biology and therapeutic responsiveness of KRAS-mutant NSCLC, Dr. Skoulidis said. Perhaps the most striking examples are co-occurring alterations in two genes—STK11 and KEAP1—which are drivers of inferior clinical outcomes with usual systemic therapies,14 including PD-1/PD-L1 inhibitors, platinum-doublet chemotherapy, chemoimmunotherapy, and second-line taxane-based regimens.

As part of an exploratory analysis of CodeBreaK 100, the impact of co-occurring mutations on clinical outcomes with sotorasib was assessed. “What we found was interesting,” Dr. Skoulidis told JNCCN 360. “When STK11 was mutated, but KEAP1 was wild-type, the benefit of treatment with sotorasib appeared to be greater; the objective response rate in this molecularly defined cohort was 50%, and median progression-free survival was 11 months. In contrast, mutations in KEAP1 may be associated with a lower likelihood of clinical response to sotorasib, although an objective response was still observed in 20% of patients bearing KEAP1-mutated tumors.

Due to the relatively small number of patients, these findings should be interpreted with caution, and results from the confirmatory phase III CodeBreaK 200 trial, which is a randomly assigned comparison of subsequent therapy with sotorasib versus docetaxel, are eagerly awaited.15 CodeBreaK 200 will allow definitive assessment of the clinical efficacy of subsequent therapy with sotorasib compared with docetaxel in patients with KRAS p.G12C–mutated NSCLC and may shed further light on molecularly defined patient subgroups that derive differential benefit from sotorasib.

Diagnostic Testing: When? For Whom? How?

When asked when and under what circumstances he would look for the p.G12C mutation in KRAS, Dr. Skoulidis responded: “I would strongly advocate for early and broad panel-based genomic profiling using next-generation sequencing. Both tissue- and plasma-based genomic profiling methods are acceptable, with high concordance for detecting KRAS p.G12C mutations. In most patients, they are clonal and truncal mutations.”

I would strongly advocate for early and broad panel-based genomic profiling using next-generation sequencing.

It should be noted that the current FDA labeling for sotorasib is for patients with locally advanced or metastatic KRAS p.G12C–mutated NSCLC after disease progression on at least one line of systemic treatment.1 Typically, these patients would receive a combination of chemotherapy and immunotherapy or, depending on PD-L1 expression, monotherapy with a PD-1/PD-L1 inhibitor, he explained. Once they have received first-line therapy and experienced disease progression, they would be eligible to receive sotorasib. However, “it is still important to know that the patient’s cancer is driven by a KRAS p.G12C mutation as early as possible,” Dr. Skoulidis told JNCCN 360. First, appropriate therapy can be considered and initiated promptly on disease progression. In addition, he pointed out, the patient may be eligible for a clinical trial exploring the first-line use of sotorasib or another KRAS p.G12C inhibitor, such as adagrasib.

In communities or cases where broad tissue-based genomic profiling is not available, Dr. Skoulidis emphasized that use of one of the two companion diagnostic tests (plasma-based Guardant360 CDx; tissue-based Therascreen KRAS RGQ PCR Kit) “should absolutely be used to screen for KRAS p.G12C mutations, especially in patients with an extensive smoking history and in those whose tumors have already been sequenced and found to be negative for mutations in other oncogenic drivers, such as EGFR, ALK, ROS1, and BRAF.” [Editor’s Note: Guardant360 CDx is a broad-based panel.] The NCCN Clinical Practice Guidelines in Oncology for NSCLC state that patients with KRAS mutations are unlikely to have other actionable mutations; therefore, they may not need further molecular testing.16 In addition, sotorasib has not been evaluated for other KRAS mutations.

Second-Line Therapy With Sotorasib

Dosing and Administration

The starting dose of sotorasib is 960 mg once a day and consists of eight 120-mg tablets, with or without food. “I usually recommend taking the tablets with food, as it seems to reduce the incidence of nausea,” Dr. Skoulidis recommended. Most patients do not report difficulty taking the tablets, but if swallowing is an issue, the tablets may be dispersed in 4 ounces of noncarbonated room temperature water. “The tablets will not dissolve completely; another 4 ounces of water can be added to disperse any residue, which should also be swallowed within a 2-hour period.”

I usually recommend taking the tablets with food, as it seems to reduce the incidence of nausea.

The notion that ingesting eight tablets may be difficult on the stomach was confirmed by Carolyn Zawislak, PA-C, who works in thoracic medical oncology at Fox Chase Cancer Center in Philadelphia.

“Although the prescribing information indicates it may be taken with or without food, most patients take sotorasib in the morning with or after a meal,” Ms. Zawislak told JNCCN 360. “The bottom line, though, is that it should be taken consistently at a time when the patient is most likely to remember to take it.”

Fewer Follow-Up Visits

Patients who have received first-line treatment with chemotherapy or immunotherapy are usually pleased with the opportunity to take an oral medication in the second line, Ms. Zawislak observed. “What they may be concerned about, though, is the reduction of follow-up visits, which brings them in contact with their care team less often than they were accustomed to with a first-line regimen. When sotorasib therapy is initiated, we ask patients to come for follow up every few weeks, but after the first or second month, those visits can be less frequent.” The sense of ownership of one’s own treatment is usually a positive factor, Ms. Zawislak said.

Polypharmacy: Keeping Things Organized

According to Ms. Zawislak, because many of these patients with NSCLC may be older and may have comorbidities for which they are receiving other oral treatments, anything that helps keep medications organized (eg, pill boxes or calendars) is useful. “That’s also true in general for ‘unscheduled’ medications, such as antiemetics or premedications for chemotherapy regimens. Pill boxes or some other system for premeasurement of tablets is particularly important for sotorasib, which requires eight tablets daily, she noted.

Adverse Effects

If patients experience side effects, Ms. Zawislak said, they may develop fairly soon after starting sotorasib. The most common adverse effects are fatigue, musculoskeletal pain, diarrhea, sometimes cough, or nausea. The more significant potential adverse events, such as hepatotoxicity, are monitored via laboratory tests.

“We don’t usually give prophylactic medications when sotorasib is prescribed,” Ms. Zawislak said, “but because these patients have already had first-line regimens, they often have antiemetics and antidiarrheals at home. Those common medications are usually sufficient for mild side effects, unlike with immunotherapy, which may require treatment with corticosteroids. Although I haven’t had to dose reduce for side effects, there are several tiers for dose reduction, the first of which is a 50% decrease.”2

Although the adverse effects of sotorasib are mostly mild and easy to manage, Dr. Skoulidis noted, treatment is rarely associated with pneumonitis/interstitial lung disease—approximately 1% incidence—and “we should have a very low threshold for holding treatment if worsening respiratory symptoms are noted. I try to be as broad and all-inclusive as possible when describing these adverse effects to patients (cough, chest tightness, fever, wheezing) and emphasize that the treatment team should be contacted immediately and treatment discontinued until these symptoms can be investigated.”

A common challenge is that these patients with lung cancer may have disease- or treatment-related respiratory symptoms at baseline, such as cough or shortness of breath. Those who have undergone radiation or have received immunotherapy may have such symptoms at baseline, before starting sotorasib and they should be meticulously documented.  “Nevertheless, any new or worsening respiratory symptoms should be called to the attention of the team right away.”

Ms. Zawislak echoed Dr. Skoulidis’ experience with side effects associated with sotorasib. “In general, I encourage patients and caregivers to call me whenever they have questions or experience something unusual. Specifically, I want to hear if they are having diarrhea or ‘new’ cough or shortness of breath, which is sometimes difficult to tease out in patients with lung cancer who may also have chronic obstructive pulmonary disease. We are pretty quick to act on anything respiratory.”

“Before I start a patient on sotorasib,” Dr. Skoulidis told JNCCN 360, “I carefully review the treatment history, with special focus on any immune-related adverse events experienced with previous treatment. There is no clear-cut evidence, but some clinicians have observed that immune-related symptoms can recur with sotorasib. I am particularly interested in whether the patient had any episodes of pneumonitis, hepatitis, or enterocolitis (eg, diarrhea) with prior immunotherapy, especially if these prior toxicities were severe.”

Dr. Skoulidis mentioned other considerations. “I might monitor such patients more frequently, obtaining liver function tests perhaps after the first week of treatment instead of after 3 weeks. I would also have a lower threshold for initiating corticosteroid treatment if I see elevated AST/ALT [aspartate aminotransferase/alanine aminotransferase] levels during sotorasib treatment. In fact, I would consider withholding sotorasib in the event of grade 2 ALT/AST elevation even in the absence of symptoms. Similarly, I would also be more apt to temporarily withhold sotorasib for a patient with a history of immune-related enterocolitis who develops diarrhea while on therapy, even if it is grade 2.”

Drug Interactions

The use of acid-reducing agents (eg, proton pump inhibitors, H2 receptor antagonists) may affect the absorption and concentration of sotorasib. These medications are used by a substantial number of patients with cancer, so this is an important interaction.

If a patient definitely needs to be on an acid reducer, Ms. Zawislak told JNCCN 360, “then we work to figure out how to keep it spaced as far apart from the sotorasib dose as possible. I’ve had a few patients where we went from a twice-daily dose of acid reducer to once daily to prevent that interaction. The more locally acting agents, such as chewable calcium carbonate tablets or combination over-the-counter products with aluminum hydroxide/magnesium hydroxide/simethicone, may be used to supplement, if necessary, but they should also be avoided for 10 hours before and 4 hours after taking sotorasib.”

When patients are ready to start sotorasib, “we need to look at their complete list of medications because there are other common medications, in addition to acid-reducing agents, that we need to think about, such as P-glycoprotein substrates,” Dr. Skoulidis cautioned. If coadministered with sotorasib, the concentration of digoxin, for instance, “may become toxic; a reduction in the dose of digoxin might be required. Conversely, coadministration with a CYP3A4 inducer can affect the concentration of sotorasib.”

A ‘Breakthrough’ Treatment

Sotorasib “represents a major breakthrough in the treatment of KRAS-mutant non–small cell lung tumors, for which there was a significant unmet need for selective, targeted therapy,” Dr. Skoulidis stated. “I would encourage patients and practitioners to seek active clinical trials, which are looking at sotorasib in several combinations with other targeted therapies to further improve the depth and durability of responses and to forestall or overcome the development of acquired resistance, such as the multi-arm CodeBreaK 101 protocol ( identifier NCT04185883). With regard to first-line use of sotorasib as monotherapy for metastatic KRAS p.G12C–mutant NSCLC (NCT04933695), it is currently being evaluated in patient subgroups (eg, those with a PD-L1 tumor proportion score of 0 and/or STK11 mutations) that fare worse with chemoimmunotherapy. Finally, examination of sotorasib in combination with platinum-based chemotherapy in the setting of early-stage, surgically resectable KRAS p.G12C–mutated NSCLC is also underway (NCT05118854).



Ferdinandos Skoulidis, MD, PhD, has served as a consultant to Amgen, Intellisphere, Navire Pharma, BeiGene, Medscape, Tango Therapeutics, and Calithera Biosciences; has ownership or stock interest in BioNTech SE and Moderna; has received institutional research grants from Mirati Therapeutics, Boehringer Ingelheim, Merck & Co, Novartis, and Pfizer; and has received speakers fees from VSPO McGill Universitaire de Montreal and RV Mais Promocao Eventos LTDS.

Carolyn Zawislak, PA-C, has served as a participant on a virtual advisory board for Eisai.



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