METHODS FOR TREATING IMMUNE REFRACTORY LUNG CANCER
The disclosure features methods for treating immune refractory lung cancer using a RAS inhibitor. The disclosure also features combination therapies for treating immune refractory lung cancer.
1 . A method of treating an immune refractory lung cancer in a subject, the method comprising administering to the subject a RAS G12C (ON) inhibitor.
2 . A method of transforming a tumor microenvironment of an immunologically cold lung cancer in a subject in need thereof, the method comprising administering to the subject a RAS G12C (ON) inhibitor.
3 . The method of claim 1 or 2 , wherein the RAS G12C (ON) inhibitor is a tri-complex RAS G12C (ON) inhibitor.
4 . A method of treating an immune refractory lung cancer in a subject, the method comprising administering to the subject a RAS inhibitor of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
A is —N(H or CH 3 )C(O)—(CH 2 )— where the amino nitrogen is bound to the carbon atom of —CH(R 10 )—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
B is absent, —CH(R 9 )—, >C═CR 9 R 9′ , or >CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3 to 8-membered heteroarylene;
L is a linker, wherein the linker is acyclic or comprises a monocyclic, fused bicyclic, fused polycyclic, bridged bicyclic, or bridged polycyclic group;
W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, a haloacetyl, or an alkynyl sulfone;
X 1 is optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) n ;
X 2 is O or NH;
X 3 is N or CH;
n is 0, 1, or 2;
R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′) 2 , S(O)R′, S(O) 2 R′, or S(O) 2 N(R′) 2 ;
each R′ is, independently, H or optionally substituted C 1 -C 4 alkyl;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl, or
R 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R 3 is absent, or
R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7′ is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 9 is H, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl, or
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 9′ is hydrogen or optionally substituted C 1 -C 6 alkyl; or
R 9 and R 9′ , combined with the atoms to which they are attached, form a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocycloalkyl;
R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl;
R 10a is hydrogen or halo;
R 11 is hydrogen or C 1 -C 3 alkyl; and
R 21 is H or C 1 -C 3 alkyl.
5 . A method of transforming a tumor microenvironment of an immunologically cold lung cancer in a subject in need thereof, the method comprising administering to the subject a RAS inhibitor of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
A is —N(H or CH 3 )C(O)—(CH 2 )— where the amino nitrogen is bound to the carbon atom of —CH(R 10 )—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
B is absent, —CH(R 9 )—, >C═CR 9 R 9′ , or >CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3 to 8-membered heteroarylene;
L is a linker, wherein the linker is acyclic or comprises a monocyclic, fused bicyclic, fused polycyclic, bridged bicyclic, or bridged polycyclic group;
W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, a haloacetyl, or an alkynyl sulfone;
X 1 is optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) n ;
X 2 is O or NH;
X 3 is N or CH;
n is 0, 1, or 2;
R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′) 2 , S(O)R′, S(O) 2 R′, or S(O) 2 N(R′) 2 ;
each R′ is, independently, H or optionally substituted C 1 -C 4 alkyl;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl, or
R 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R 3 is absent, or
R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7′ is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 9 is H, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl, or
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 9′ is hydrogen or optionally substituted C 1 -C 6 alkyl; or
R 9 and R 9′ combine with the atom to which they are attached to form a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocycloalkyl;
R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl;
R 10a is hydrogen or halo;
R 11 is hydrogen or C 1 -C 3 alkyl; and
R 21 is H or C 1 -C 3 alkyl.
6 . The method of claim 5 , wherein the subject is resistant to an immune checkpoint inhibitor prior to transformation of the tumor microenvironment.
7 . The method of claim 5 or 6 , wherein administering the RAS inhibitor transforms the tumor microenvironment thereby sensitizing the cancer to treatment with an immune checkpoint inhibitor.
8 . The method of any one of claims 1 to 7 , further comprising administering to the subject a SHP2 inhibitor.
9 . A method of treating an immune refractory lung cancer in a subject, the method comprising administering to the subject a RAS G12C (ON) inhibitor, a SHP2 inhibitor, and an immune checkpoint inhibitor.
10 . A method of transforming a tumor microenvironment of an immunologically cold lung cancer in a subject in need thereof, the method comprising administering to the subject a RAS G12C (ON) inhibitor, a SHP2 inhibitor, and an immune checkpoint inhibitor.
11 . The method of any one of claims 1 to 3 and 8 to 10 , wherein the RAS G12C (ON) inhibitor is a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
A is —N(H or CH 3 )C(O)—(CH 2 )— where the amino nitrogen is bound to the carbon atom of —CH(R 10 )—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
B is absent, —CH(R 9 )—, >C═CR 9 R 9′ , or >CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3 to 8-membered heteroarylene;
L is a linker, wherein the linker is acyclic or comprises a monocyclic, fused bicyclic, fused polycyclic, bridged bicyclic, or bridged polycyclic group;
W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, a haloacetyl, or an alkynyl sulfone;
X 1 is optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) n ;
X 2 is O or NH;
X 3 is N or CH;
n is 0, 1, or 2;
R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′) 2 , S(O)R′, S(O) 2 R′, or S(O) 2 N(R′) 2 ;
each R′ is, independently, H or optionally substituted C 1 -C 4 alkyl;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl, or
R 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R 3 is absent, or
R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7′ is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 9 is H, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl, or
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 9′ is hydrogen or optionally substituted C 1 -C 6 alkyl; or
R 9 and R 9′ combine with the atom to which they are attached to form a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocycloalkyl;
R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl;
R 10a is hydrogen or halo;
R 11 is hydrogen or C 1 -C 3 alkyl; and
R 21 is H or C 1 -C 3 alkyl.
12 . The method of any one of claims 1 to 11 , wherein the RAS inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof.
13 . The method of any of claims 1 to 12 , wherein the RAS inhibitor is
or a pharmaceutically acceptable salt thereof.
14 . The method of any one of claims 1 to 8 and 11 to 13 , further comprising administering to the subject an immune checkpoint inhibitor.
15 . A method of treating an immune refractory lung cancer in a subject, the method comprising administering to the subject a RAS inhibitor, a SHP2 inhibitor, and an immune checkpoint inhibitor, wherein the RAS inhibitor is:
or a pharmaceutically acceptable salt thereof, and
the SHP2 inhibitor is:
or a pharmaceutically acceptable salt thereof.
16 . The method of any one of claims 9, 10, 14, and 15 , wherein the immune checkpoint inhibitor is a PD-1 inhibitor.
17 . The method of any one of claims 1 to 16 , wherein the subject has previously been administered an immune checkpoint inhibitor.
18 . The method of any one of claims 1 to 17 , wherein the subject is resistant to treatment with an immune checkpoint inhibitor.
19 . The method of claim 18 , wherein the subject has acquired resistance to treatment with an immune checkpoint inhibitor.
20 . The method of any one of claims 1 to 19 , wherein administering the RAS inhibitor sensitizes the cancer to treatment with an immune checkpoint inhibitor.
21 . The method of any one of claims 8 to 20 , wherein the inhibitors are administered simultaneously or sequentially.
22 . The method of any one of claims 8 to 21 , wherein the inhibitors are administered as a single formulation or in separate formulations.
23 . The method of any one of claims 1 to 22 , wherein the subject has one or more tumors with a low tumor mutational burden.
24 . The method of any one of claims 1 to 23 , wherein the subject has one or more microsatellite stable tumors.
25 . The method of any one of claims 1 to 24 , wherein the subject has one or more tumors with low microsatellite instability.
26 . The method of any one of claims 1 to 25 , wherein the subject has one or more tumors with a low tumor immune infiltrate.
27 . The method of any one of claims 1 to 26 , wherein administering the RAS inhibitor alters the tumor immune infiltrate relative to the tumor immune infiltrate in the absence of the RAS inhibitor.
28 . The method of claim 26 or 27 , wherein the tumor immune infiltrate comprises antigen-presenting cells, myeloid cells, or lymphoid cells.
29 . The method of any one of claims 1 to 28 , wherein administering the RAS inhibitor alters the anti-tumor immune response.
30 . The method of any one of claims 1 to 29 , wherein administering the RAS inhibitor alters the tumor microenvironment relative to the tumor microenvironment in the absence of the RAS inhibitor.
31 . The method of any one of claims 1 to 30 , wherein administering the RAS inhibitor transforms an immunologically cold tumor into an immunologically hot tumor.
32 . The method of any one of claims 1 to 31 , wherein the method reduces tumor size or inhibits tumor growth.
33 . The method of any one of claims 1 to 32 , wherein the immune refractory lung cancer is non-small cell lung cancer or small-cell lung cancer.
34 . The method of any one of claims 1 to 33 , wherein the immune refractory lung cancer comprises a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation.