Drug Trials Snapshot: LUMAKRAS

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.

Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the LUMAKRAS Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).

Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).

LUMAKRAS (SOTORASIB)
(Loo-mah-kras)
Amgen
Original Approval date: 05/28/2021

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

LUMAKRAS is a drug used to treat adult patients with non-small cell lung cancer (NSCLC) that is locally advanced or has spread to other parts of the body (metastatic). It should be used in patients who have been treated with at least one prior type of therapy and whose cancer has a certain type of genetic mutation (KRAS G12C).

How is this drug used?

LUMAKRAS is a tablet. Eight tablets (960 mg total) are taken by mouth each day with or without food.

Who participated in the clinical trials?

The FDA approved LUMAKRAS based on evidence from one clinical trial of patients with non-small cell lung cancer (NSCLC). The same trial was used to assess the efficacy of LUMAKRAS in 124 patients and the safety of LUMAKRAS in 204 patients: therefore the number of patients representing efficacy findings may differ from the number of patients representing safety findings due to different pools of study participants analyzed for efficacy and safety. The trial was conducted at 46 of sites in 10 countries (Australia, Austria, Belgium, Canada, France, Germany, Japan, Korea, Switzerland, and the United States).

What are the benefits of this drug?

Approximately 36% of patients (37 of 124 patients) treated with LUMAKRAS in the clinical study CodeBreaK 100 had partial shrinkage of their cancer, including two patients with complete shrinkage. Shrinkage lasted more than 6 months for 58% of patients who had a response to LUMAKRAS.

LUMAKRAS was approved under the FDA’s accelerated approval program, which provides earlier patient access to a promising new drug while the company continues to conduct clinical trials to confirm that the drug works well.

What are the benefits of this drug (results of trials used to assess efficacy)?

Table 3 summarizes efficacy results based on overall response rate as determined by a Blinded Independent Review Committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Table 3. Efficacy Results in Patients With KRAS G12C-Mutated NSCLC Previously Treated With at Least One Prior Therapy

Efficacy Parameter	LUMAKRAS N=124
Objective response rate (95% CI)a	36 (28, 45)
Complete response rate (%)	2
Partial response rate (%)	35
Duration of responsea
Medianb, months (range)	10.0 (1.3+, 11.1)
Patients with duration ≥6 monthsc (%)	58

Source: Adapted from FDA review
Abbreviations: CI, confidence interval; NSCLC, non-small cell lung cancer
+ censoring
^a Assessed by Blinded Independent Central Review (BICR)
^b Estimate using Kaplan Meier method
^c Observed proportion of patients with duration of response beyond landmark time

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

• Sex: LUMAKRAS appears to work similarly in males and females.
• Race: The number of patients of races other than White was small; therefore, differences in how LUMAKRAS worked among races could not be determined.
• Age: LUMAKRAS appears to work similarly in patients below and above 65 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Table 4. Summary of Overall Response in Subgroups Per Blinded Independent Central Review

Demographic Subgroup	N	ORR by BICR % (95% CI)
Sex
Female	62	31 (20, 44)
Male	62	42 (30, 55)
Age at diagnosis
<65 years	65	31 (20, 43)
≥65 years	59	42 (30, 56)
Race
Asian	18	17 (3.6, 41)
White	102	40 (31, 50)

Source: Adapted from FDA review
Abbreviations: BICR, blinded independent central review; CI, confidence interval; ORR, objective response rate

What are the possible side effects?

The most common side effects observed with LUMAKRAS include diarrhea, muscle pain, nausea, feeling tired, and cough.

LUMAKRAS increased liver enzyme levels in the blood and may cause liver injury. Inflammation of the lung (interstitial lung disease or pneumonitis) can also occur.

What are the possible side effects (results of trials used to assess safety)?

Table 5. Adverse Reactions (≥10%) of Patients With KRAS G12C Mutated NSCLC Who Received LUMAKRAS in CodeBreaK 100*

Adverse Reaction	LUMAKRAS N=204
	All Grades (%)	Grade 3 to 4 (%)
Gastrointestinal disorders
Diarrhea	42	5
Nausea	26	1
Vomiting	17	1.5
Constipation	16	0.5
Abdominal paina	15	1.0
Hepatobiliary disorders
Hepatotoxicityb	25	12
Respiratory
Coughc	20	1.5
Dyspnead	16	2.9
Musculoskeletal and connective tissue disorders
Musculoskeletal paine	35	8
Arthralgia	12	1.0
General disorders and administration site conditions
Fatiguef	26	2.0
Edemag	15	0
Metabolism and nutrition disorders
Decreased appetite	13	1.0
Infections and infestations
Pneumoniah	12	7
Skin and subcutaneous tissue disorders
Rashi	12	0

Source: Adapted from FDA review
* Grading defined by NCI CTCAE version 5.0
^a Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower
^b Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug induced liver injury, hepatitis, hepatotoxicity, liver function test increased, transaminases increased
^c Cough includes cough, productive cough, and upper airway cough syndrome
^d Dyspnea includes dyspnea and dyspnea exertional
^e Musculoskeletal pain includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non cardiac chest pain, and pain in extremity
^f Fatigue includes fatigue and asthenia
^g Edema includes generalized edema, localized edema, edema, edema peripheral, periorbital edema, and testicular edema
^h Pneumonia includes pneumonia, pneumonia aspiration, pneumonia bacterial, and pneumonia staphylococcal
ⁱ Rash includes dermatitis, dermatitis acneiform, rash, rash maculopapular, rash pustular
Abbreviations: NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NCSLC, non-small cell lung cancer

Were there any differences in side effects of the clinical trials among sex, race, and age?

• Sex: The occurrence of side effects was generally similar in males and females.
• Race: The number of patients of races other than White was small; therefore, differences in the occurrences of side effects worked among races could not be determined.
• Age: The occurrence of side effects was generally similar in patients below and above 65 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

There were no major differences in the type, frequency, and severity of adverse events observed in patient subgroups including age, race, and sex when compared to the overall study population.

Table 1. Overview of Adverse Reactions by Sex, Race, Age, Ethnicity, and Country In Patients With KRAS G12C-Mutated NSCLC Who Received LUMAKRAS in CodeBreaK 100

Demographic Variable	LUMAKRAS N=204
	All Patients n (%)	All Grades n/Ns (%)	Grades 3 to 4 n/Ns (%)
Sex
Female	112 (54.9)	111/112 (99.1)	62/112 (55.4)
Male	92 (45.1)	90/92 (97.8)	51/92 (55.4)
Race
Asian	30 (14.7)	28/30 (93.3)	15/30 (50.0)
Black or African American	5 (2.5)	5/5 (100)	3/5 (60.0)
Other	5 (2.5)	5/5 (100)	2/5 (40.0)
White	164 (80.4)	163/164 (99.4)	93/164 (56.7)
Age at diagnosis
<65 years	90 (44.1)	89/90 (98.9)	53/90 (58.9)
≥65 to <75 years	89 (43.6)	87/89 (97.8)	47/89 (52.8)
≥75 to <85 years	24 (11.8)	24/24 (100)	13/24 (54.2)
≥85 years	1 (0.5)	1/1 (100)	0/1 (0)
Ethnicity
Hispanic or Latino	3 (1.5)	3/3 (100)	0/3 (0)
Not Hispanic or Latino	190 (93.1)	187/190 (98.4)	109/190 (57.4)
Not reported	11 (5.4)	11/11 (100)	4/11 (36.4)
Country
United States	142 (69.6)	62/62 (100)	35/62 (56.5)
Non-United States	62 (30.4)	139/142 (97.9)	78/142 (54.9)

Source: FDA reviewer’s analysis
Abbreviation: N, number of patients in the safety population; n, number of patients with given characteristic; Ns, total number of patients in each category

DEMOGRAPHICS SNAPSHOT

Figure 1 summarizes how many male and female patients were enrolled in the combined clinical trials used to evaluate the efficacy of LUMAKRAS.

Figure 1. Baseline Demographics by Sex (Safety Population)

Source: Adapted from FDA review

Figure 2. Baseline Demographics by Race (Safety Population)

Source: Adapted from FDA review

Figure 3. Baseline Demographics by Age (Safety Population)

Source: Adapted from FDA review

Who participated in the trials?

Table 1. Study CodeBreaK 100 Baseline Demographics and Disease Characteristics in the Safety Population

Demographic and Disease Characteristic, n (%)	CodeBreaK 100 N=204
Sex
Female	112 (55)
Male	92 (45)
Age at diagnosis
<65 years	90 (44)
≥65 years	114 (56)
Race
Asian	30 (15)
Black or African American	5 (2.5)
Other	5 (2.5)
White	164 (80)
Ethnicity
Hispanic or Latino	3 (2)
Not Hispanic or Latino	190 (93)
Not reported	11 (5)
Region
Asia	17 (8.3)
Europe	31 (15)
North America	148 (73)
Other
Baseline ECO
0	58 (28)
1	144 (71)
≥2
Smoking history
Current	20 (10)
Former	168 (82)
Never	13 (6)
Not reported	3 (2)
Number of prior lines of therapy
0	28 (14)
1	73 (36)
2	59 (29)
≥3	44 (21)
Prior platinum-based chemotherapy
No	32 (16)
Yes	172 (84)
Prior PD-1 or PD-L1
No	43 (21)
Yes	161 (79)

Source: Adapted from FDA review

Table 2. Study CodeBreaK 100 Baseline Demographics and Disease Characteristics in the Efficacy Population

Demographics and Disease Characteristic, n (%)	CodeBreaK 100 N=124
Sex
Female	62 (50)
Male	62 (50)
Age at diagnosis, median [range]	64.0 [37.0, 80.0]
<65 years	65 (52)
≥65 years	59 (48)
Race
Asian	18 (15)
Black or African American	2 (2)
Other	2 (2)
White	102 (82)
Ethnic
Hispanic or Latino	2 (2)
Not Hispanic or Latino	114 (92)
Not reported	8 (6)
Region
Asia	11 (9)
Europe	29 (23)
North America	79 (64)
Other	5 (4)
Baseline ECOG
0	37 (30)
1	87 (70)
Histopathology at baseline
Non-squamous	123 (99)
Squamous	1 (1)
Smoking history
Current	15 (12)
Former	100 (81)
Never	6 (5)
Not reported	3 (2)
Disease stage at screening
Stage III	5 (4)
Stage IV	119 (96)
Number of prior line of therapy
1	53 (43)
2	43 (35)
3	28 (23)
Liver metastasis at baseline
No	98 (79)
Yes	26 (21)
Brain metastasis at baseline
No	98 (79)
Yes	26 (21)
Bone metastasis at baseline
No	65 (52)
Yes	59 (48)
Prior platinum-based chemotherapy
No	13 (10)
Yes	111 (90)
Prior PD-1 or PD-L1
No	11 (9)
Yes	113 (91)
Differentiation at baseline
Moderately differentiated	15 (12)
Poorly differentiated	24 (19)
Unknown	79 (64)
Well differentiated	6 (5)

How were the trials designed?

LUMAKRAS was evaluated in 1 non-randomized, dose escalation and dose expansion clinical trial (CodeBreaK 100) in patients with non-small cell lung cancer (NSCLC). There were 124 patients with NSCLC included in the primary efficacy population, while 204 patients with NSCLC were included in the primary safety population. The primary endpoint of the trial was objective response rate (ORR).

How were the trials designed?

CodeBreaK 100 is a single-arm, non-randomized, dose escalation and dose expansion study of LUMAKRAS in patients with advanced solid tumors including NSCLC that harbored a KRAS G12C mutation and had received prior therapies. In the dose escalation portion of the study, patients were treated in cohorts of increasingly higher doses of LUMAKRAS. These doses ranged from 180 mg daily to 960 mg daily. The primary objective of the dose escalation portion of CodeBreaK 100 was to evaluate the safety and tolerability of LUMAKRAS in patients and to determine the dose that should be used in the dose expansion portion of the study. The 960 mg daily dose was selected for the dose expansion portion of the study and 126 patients with KRAS G12C mutated NSCLC were treated with this dose while being evaluated for objective response rate, the primary endpoint of the study. A key secondary endpoint of CodeBreak 100 was duration of response.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

LINK TO LUMAKRAS PACKAGE INSERT:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214665s000lbl.pdf

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